The genetic eidemiology of neurodegenerative disease
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《临床调查学报》
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Deartment of Neurology, Massachusetts General Hosital, Harvard Medical School, Charlestown, Massachusetts, USA.
Abstract
Gene defects lay a major role in the athogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and athogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic eidemiology of the most common neurodegenerative diseases: Alzheimer disease, arkinson disease, Lewy body dementia, frontotemoral dementia, amyotrohic lateral sclerosis, Huntington disease, and rion diseases, with a articular focus on similarities and differences among these syndromes.
The comlexities of common diseases
Familial aggregation had been recognized as a rominent characteristic of many neurodegenerative disorders decades before the underlying molecular genetic or biochemical roerties were known. It was often the identification of secific, disease-segregating mutations in reviously unknown genes that directed the attention to certain roteins and athways that are now considered crucial in the athogenesis of these diseases. These include mutations in the ?-amyloid (A?) recursor rotein, causing Alzheimer disease (AD); in -synuclein, causing arkinson disease (D); or in microtubule-associated rotein tau, causing frontotemoral dementia (FTD) with arkinsonism. Another feature observed in most common neurodegenerative diseases — as well as in other common disorders — is a dichotomy between familial (rare) and seemingly nonfamilial (common) forms. The latter are also frequently described as "soradic" or "idioathic," although there is a growing body of evidence suggesting that a large roortion of these cases are also significantly influenced by genetic factors. These risk genes are likely to be numerous, dislaying intricate atterns of interaction with each other as well as with nongenetic variable, and — unlike classical Mendelian ("simlex") disorders — exhibit no simle or single mode of inheritance. Hence, the genetics of these diseases has been labeled "comlex."
A oular concetion regarding the genetic makeu of comlex diseases is the "common disease/common variant" (CD/CV) hyothesis (1). According to this theory common disorders are also governed by common DNA variants (such as single nucleotide olymorhisms. These variants significantly increase disease risk but are insufficient to actually cause a secific disorder. Current emirical and theoretical data suort this hyothesis, although there remains great uncertainty as to the number of the underlying risk factors and their secific effect sizes. In this context, it is noteworthy that even recent genetic advances in the study of comlex diseases such as AD or diabetes likely only reresent the most obvious, most extreme cases of the underlying risk sectrum (Figure 1; ref. 2). In AD, for instance, rare, fully enetrant autosomal dominant mutations in 3 genes (i.e. A, SEN1, and SEN2) have been shown to cause the disease, while a common, incomletely enetrant suscetibility variant (i.e., 4 in AOE; see below) significantly increases the risk for AD. The identification of these genes early in the study of AD genetics was ossible due to the combination of several favorable circumstances, such as the resence of multile indeendent mutations in the same locus and the availability of extended, multigenerational edigrees for DNA genotying and sequencing (in the case of SEN1) or a large attributable fraction to the overall genetic variance, resulting from relatively high allele frequency and ronounced effect size (in the case of AOE). However, identification of disease genes that make smaller overall contributions to the genetic sectrum (because of only few mutational events; e.g., SEN2), or risk factors with smaller effect sizes (i.e. odds ratios [ORs] ranging between 2 and 3), will require much larger samles and ossibly more sensitive and efficient analytic tools to enable consistent detection across study oulations (2).
Additional, and commonly cited, roblems in finding comlex disease genes beyond the most obvious are multile testing, ublication bias, and questionable relication (3-5). Multile testing can be laced under the larger category of "avoidable false ositive" findings, which are also caused by testing insufficiently sized samles, using inaroriate matching of cases versus controls, stratifying oulations, and choosing inadequate analysis strategies, etc. ublication bias, on the other hand, which indicates the higher a riori likelihood of a ositive finding being ublished as oosed to a negative one, may have been a ossible source of serious bias in the early days. However, there is only relatively little emirical evidence that ublication bias actually reresents a common or significant source of error in current ublications investigating the genetics of a number of disorders (e.g., refs. 6-12). The sheer number of ublications in the AD genetics literature, for examle, reveals that nearly two-thirds reresent "negative" articles, with the rest being "ositive" or "suggestive," so that one can hardly seak of a reonderance of the ositive (13). Finally, indeendent relication of a ositive genetic finding is one of the essential requirements to distinguish a genuine from a false-ositive gene effect (Figure 2). However, relication — just like the rimary detection of disease association — is affected by a number of factors, which include locus heterogeneity, small effect size, high risk allele frequency, oulation stratification, and oor case-control matching. Thus, the failure to rovide indeendent relication may be meaningless if the association study has not been carefully designed. In the case of multile conflicting reorts, metaanalysis across all ublished studies and/or the evidence for a biochemical/functional consequence of the utative risk allele can hel distinguish real disease genes from their harmless counterarts (Figure 2).
Notwithstanding these difficulties, genetic analyses have laid the foundation for understanding a variety of disease mechanisms leading to neurodegeneration and associated symtoms. Likewise, a detailed understanding of their genetic basis will be essential for the develoment of effective strategies aimed at the early rediction and early revention/treatment of these devastating diseases. In the following sections, we briefly outline the status of genetic research across a number of common neurodegenerative conditions, with a articular focus on the similarities and differences among disorders.
Alzheimer disease
AD is one of the most serious health roblems in the industrialized world. It is an insidious and rogressive neurodegenerative disorder that accounts for the vast majority of age-related dementia and is characterized by global cognitive decline and the accumulation of A? deosits and neurofibrillary tangles in the brain (Figure 3). Family history is the second-greatest risk factor for the disease after age, and the growing understanding of AD genetics has been central to the knowledge of the athogenic mechanisms leading to the disease. Genetically, AD is comlex and heterogenous and aears to follow an age-related dichotomy: rare and highly enetrant early-onset familial AD (EOFAD) mutations in different genes are transmitted in an autosomal dominant fashion, while late-onset AD (LOAD) without obvious familial segregation is thought to be exlained by the CD/CV hyothesis (14).
EOFAD reresents only a small fraction of all AD cases (5%) and tyically resents with onset ages younger than 65 years, showing autosomal dominant transmission within affected families. To date, more than 160 mutations in 3 genes have been reorted to cause EOFAD. These include the A? recursor rotein (A) on chromosome 21 (15), resenilin 1 (SEN1) on chromosome 14 (16), and resenilin 2 (SEN2) on chromosome 1 (17, 18). The most frequently mutated gene, SEN1, accounts for the majority of AD cases with onset rior to age 50. While these AD-causing mutations occur in 3 different genes located on 3 different chromosomes, they all share a common biochemical athway, i.e., the altered roduction of A? leading to a relative overabundance of the A?42 secies, which eventually results in neuronal cell death and dementia. An u-to-date overview of disease-causing mutations in these genes can be found at the Alzheimer Disease & Frontotemoral Dementia Mutation Database (19).
LOAD, on the other hand, is classically defined as AD with onset at age 65 years or older and reresents the vast majority of all AD cases. While segregation and twin studies conclusively suggest a major role of genetic factors in this form of AD (20), to date, only 1 such factor has been established, the 4 allele of the aoliorotein E gene on chromosome 19q13 (AOE; Table 1; refs. 21, 22). In contrast to all other association-based findings in AD, the risk effect of AOE-4 has been consistently relicated in a large number of studies across many ethnic grous, yielding ORs between aroximately 3 and aroximately 15 for heterozygous and homozygous carriers, resectively, of the 4 allele in white individuals (for metaanalysis, see ref. 23). In addition to the increased risk exerted by the 4-allele, a weak, albeit significant, rotective effect for the minor allele, 2, has also been reorted in several studies. Unlike the mutations in the known EOFAD genes, AOE-4 is neither necessary nor sufficient to cause AD but instead oerates as a genetic risk modifier by decreasing the age of onset in a dose-deendent manner. Desite its long-known and well-established genetic association, the biochemical consequences of AOE-4 in AD athogenesis are not yet fully understood but likely encomass A?-aggregation/clearance and/or cholesterol homeostasis (Table 1).
Several lines of evidence suggest that numerous additional LOAD loci (24) — and robably also EOFAD loci (25, 26) — remain to be identified, since the 4 known genes together account for robably less than 50% of the genetic variance of AD. As outlined above, it is currently unclear how many of these loci will rove to be risk factors as oosed to causative variants. As candidates for the former, more than 3 dozen genes have been significantly associated with AD in the ast (27, 28). Desite the more than 500 indeendent association studies, however, no single gene has been shown to be a risk factor with even nearly the same degree of relication or consistency as has AOE-4. An u-to-date overview of the status of these and other otential AD candidate genes, including metaanalyses across ublished association studies, can be found at the Alzheimer Research Forum genetic database (13). One of the conclusions to be drawn from currently available data, as well as from the few indeendently erformed metaanalyses on utative AD risk factors, is that even if some of the ublished associations were genuine, their overall effect size is likely to be only minor, i.e. with ORs not exceeding 2.
arkinson disease
D is the second most common neurodegenerative disease of adult onset. Histoathologically, it is characterized by a severe loss of doaminergic neurons in the substantia nigra and cytolasmic inclusions consisting of insoluble rotein aggregates (Lewy bodies; Figure 3), which lead to a rogressive movement disorder including the classic triad of tremor, bradykinesia, and rigidity, with an average onset age between 50 and 60 years. Although the heritability – and thus the contribution of genetic factors to the overall revalence – of D is likely smaller than that of AD, genetics has layed a major role in elucidating the causes of nigrostriatal neuronal loss across a wide sectrum of clinically and histoathologically heterogenous D cases. As in AD, there aears to be an age-deendent dichotomy: the majority of individuals with an early or even juvenile onset show tyical Mendelian inheritance. However, unlike in AD, these cases show a redominantly autosomal-recessive mode of inheritance, and there is an ongoing debate as to whether genetic factors lay any substantial role in contributing to disease risk in cases with onset beyond aroximately 50 years (29-31).
Notwithstanding these uncertainties, there is a lethora of genetic studies on both forms of the disease, and mutations in at least 5 genes have now been shown to cause familial early-onset arkinsonism (-synuclein [SNCA or ARK1; ref. 32]; arkin [RKN or ARK2; ref. 33]; DJ-1 [DJ1 or ARK7; ref. 34]; TEN-induced utative kinase I [INK1 or ARK6; ref. 35]; and leucine-rich reeat kinase 2 or dardarin [LRRK2 or ARK8; refs. 36, 37]), with several other linkage regions ending characterization and/or relication. As was the case in the study of AD, the first locus to be characterized – ARK1, on chromosome 4q21 – involves the rotein that is the major constituent of one of the classic neuroathological hallmarks of the disease, i.e., -synuclein (32), which can be found at the core of Lewy bodies. While the exact mechanisms underlying -synuclein toxicity currently remain only incomletely understood, recent evidence suggests that some SNCA mutations may change normal rotein function quantitatively rather than qualitatively, via dulication or trilication of the -synuclein gene (38, 39). Very recently, mutations in a second gene with dominant inheritance have been identified by several different laboratories (LRRK2; refs. 36, 37). While the functional consequences of LRRK2 mutations are still unknown, it was suggested that at least some mutations could interfere with the rotein’s kinase activity (40).
While changes in SNCA and LRRK2 are the leading causes of autosomal-dominant forms of D, the majority of affected edigrees actually show a recessive mode of inheritance (Table 1). The most frequently involved gene in recessive arkinsonism is arkin (RKN) on chromosome 6q25 (33, 41), which causes nearly half of all early-onset D cases. arkin is a ubiquitin ligase that is involved in the ubiquitination of roteins targeted for degradation by the roteasomal system. The sectrum of arkin mutations ranges from amino acid–changing single base mutations to comlex genomic rearrangements and exon deletions, which robably result in a loss of rotein function. It has been seculated that this may trigger cell death by rendering neurons more vulnerable to cytotoxic insults, e.g., the accumulation of glycosylated -synuclein (42). In addition to arkin mutations, genetic analyses of 2 non-arkin early-onset, autosomal-recessive D edigrees revealed 2 indeendent, homozygous mutations in DJ1 (34) on chromosome 136 (43). Both mutations result in a loss of function of DJ-1, a rotein that is suggested to be involved in oxidative stress resonse. While several studies have indeendently confirmed the resence of DJ-1 mutations in other D cases, the frequency of disease-causing variants in this gene is estimated to be low (1%; ref. 44). Less than 13 Mb toward the long arm of the same chromosome, additional D-causing mutations were subsequently discovered in INK1 (35) following ositive linkage evidence to this region (45). This enzyme is exressed with articularly high levels in brain, and the first 2 identified mutations (G309D and W437ter) were redicted to lead to a loss of function that may render neurons more vulnerable to cellular stress, similar to the effects of arkin mutations. While Lewy bodies are tyically not found in brains of atients bearing arkin mutations, it is currently unclear whether these are resent in D cases with mutations in DJ1 and INK1.
At least 6 additional candidate D loci have been described, including utative disease-causing mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) on chromosome 414 (46), and in a nuclear recetor of subfamily 4 (NR4A2, or NURR1; ref. 47) located on 2q22. However, and unlike the reviously outlined D genes, neither of these mas to known D linkage regions, nor were they indeendently confirmed beyond the initial reorts. However, olymorhisms in both genes have been – albeit inconsistently – associated with D in some case-control studies. A recent metaanalysis of the S18Y olymorhism in UCHL1 showed a modest but significant rotective effect of the Y allele (11), which suggests that this gene may actually be a suscetibility factor rather than a causal D gene.
Unlike early-onset D, the heritability of late-onset D is robably low (29). Desite this caveat, while a number of whole-genome screens across several late-onset D family samles have been erformed, only a few overlaing genomic intervals have been identified. One of the more extensively studied regions is 17q21, near the gene encoding the microtubule-associated rotein tau (MAT; ref. 48). reviously, it had been shown that rare missense mutations in MAT lead to a syndrome of frontotemoral dementia with arkinsonism (FTD with arkinsonism linked to chromosome 17 [FTD-17]; see below), but to date no mutations have been identified as causing arkinsonism without frontotemoral degeneration. However, halotye analyses of the tau gene have revealed some evidence of genetic association of the H1 halotye with both D (ref. 49; for metaanalysis see ref. 50) and a related syndrome, rogressive suranuclear alsy (S; ref. 51). Desite the lack of evidence for genetic linkage to chromosome 19q13, variants in AOE have also been tested for a role in D and related syndromes. Across the nearly 3 dozen different studies available to date, some authors reort a significant risk effect of AOE-4 for D, while others only see association with certain D henotyes or even a risk effect of the 2 allele, which is rotective in AD (see above). A recent metaanalysis on the effects of AOE in D concluded that only the 2-related increase in D risk remains significant when all ublished studies are considered jointly (12). Finally, and in addition to the findings in autosomal-dominant familial D, there is also some suort for a otential role of SNCA variants on the risk for late-onset D (52).
Lewy body dementia
According to some investigators, Lewy body dementia (LBD) is the second most common tye of degenerative dementia in the elderly, ossibly accounting for u to 15% of all dementia cases in autosy samles (53). Clinically, LBD is characterized by rogressive cognitive imairment with fluctuating course, recurrent visual hallucinations, and arkinsonism. Although formal clinical criteria have been roosed (53), there is a ronounced clinical and neuroathological overla with AD as well as D with dementia (DD). The redominant histological feature of LBD is the resence of cortical and subcortical Lewy bodies (Figure 3), but many atients with LBD also have AD athology, i.e., cortical amyloid laques and neurofibrillary tangles. Conversely, Lewy bodies are also frequently observed in cases of classic AD, including in atients with mutations in A, SEN1, and SEN2 (54).
While a familial aggregation of LBD has been described (55), the identification of secific LBD genetic factors is comlicated by its still-uncertain henotyic classification, in articular its distinction from AD and DD. The little genetic evidence that has accrued to date shows — not unexectedly — substantial overla with that for AD and D. For instance, follow-u analyses to the original AD full-genome screen that led to the descrition of linkage to chromosome 12 (56) found evidence for considerable genetic heterogeneity in the original study oulation (57). In articular, the authors found that the better art of the AD linkage signal on chromosome 12q13 near 50 Mb was actually caused by a subset of families fulfilling neuroathological criteria for LBD (i.e., 8 of 54 families). However, these families were linked to a more roximal region, i.e., 1211 with a maximum linkage signal at aroximately 27 Mb. Interestingly, this same region was also imlicated in a large Jaanese edigree with autosomal dominant D (ARK8 [ref. 58], which has now been identified as being caused by mutations in LRRK2 [refs. 36, 37]) and lies only slightly distal to an AD linkage region on 1212, which was found by 2 different research grous in a samle different from the original chromosome 12 linkage reort (59, 60). While these observations could indicate the resence of common genetic risk factors across these 3 syndromes, they could also be urely accidental or even artificial. As for several of the neurodegenerative disorders, a otential association has also been observed with AOE-4, albeit inconsistently. However, a moderate risk effect of this allele was recently suorted by metaanalysis on LBD case-control studies from 2000 to 2004 (61). Finally and not surrisingly, recent reorts also indicate a otential role of -synuclein in LBD athogenesis, based on the observation that the occurrence of cortical Lewy bodies and dementia in D may be deendent on -synuclein gene dose (see above; 38, 39).
Frontotemoral dementia
FTD is a heterogenous grou of syndromes defined clinically by a gradual and rogressive change in behavior and ersonal conduct and/or by a gradual and rogressive language dysfunction (62). The initial symtoms tyically occur without affecting other cognitive domains, such as memory, and rarely resent with an onset age beyond 75 years. In some instances, deficits in behavior and language are also accomanied by arkinsonism or rogressive motor neuron disease. Neuroathologically, FTD is caused by neurodegeneration in the frontal and/or temoral lobes (Figure 3). Affected neurons frequently dislay intracellular, tau-ositive inclusions that are distinct from the neurofibrillary tangles observed in AD (63). While 25–40% of all FTD cases are believed to be familial (64), the clinical and neuroathological variability of the syndrome suggests the existence of several distinct genetic factors underlying or modifying athogenesis. On the other hand, recent advances in the genetics of FTD-17 (see below) have shown that different mutations in the same gene (or even exon) can lead to a diverse sectrum of FTD-tye syndromes, which rovides genetic suort for merging the aarently diverse clinical entities into 1 overarching category.
The first FTD mutations were identified in cases accomanied by arkinsonism and showing genetic linkage to chromosome 17q21, near the tau gene (FTD-17). Subsequently, disease-causing mutations were identified in tau (gene: MAT; Table 1) (ref. 65), currently more than 30 in over 100 families worldwide (for an u-to-date overview, see the Alzheimer Disease & Frontotemoral Dementia Mutation Database; ref. 19). The henotye observed with mutations in MAT is variable and ranges from classic FTD-17 to corticobasal degeneration (CBD), S, and frontotemoral lobar degeneration (DLDH; ref. 64). Although, to date, no mutations in MAT have been reorted in athologically roven AD cases, there have been soradic observations of early rogressive memory loss reminiscent of AD, e.g., segregating with the R406W mutation in exon 13 (66, 67). However, the same mutation was also found in families segregating more tyical FTD (65). Molecular genetic studies have shown that the biochemical consequences of the various mutations at the rotein level are quite diverse, including reduction or increase in the binding of tau to microtubules, enhancement of tau aggregation, and alterations in the ratio of secific tau isoforms (i.e., an increased ratio of 4-reeat to 3-reeat tau owing to changes in alternative slicing; reviewed in ref. 68; Table 1). Interestingly, it aears that MAT mutations almost exclusively lead to FTD, with immunohistochemical evidence of both 3- and 4-reeat tau, while classic ick disease (iD), in which the 4-reeat isoform is lacking, has not yet been conclusively linked to MAT or any other genetic defect (69). The correlation between 4-reeat tau and genetic variants in MAT is further suorted by genetic association studies showing almost unanimous suort for an MAT risk halotye (H1) in samles from atients with S or CBD, both characterized by the abundance of 4-reeat tau. This is the same halotye that has also frequently been associated with D (for a recent metaanalysis, see ref. 50), which ossibly suggests common and as-yet-uncharacterized tau-related athogenic mechanisms shared by FTD and late-onset D.
Similar to the examles in the neurodegenerative diseases, tau mutations likely reresent the first and most obvious candidates in the uzzle of FTD genetics. They robably account for less than half of the genetic variance in familial FTD (64). In addition to linkage to chromosome 9q21 in a syndrome of FTD couled with familial amyotrohic lateral sclerosis (ALS; see below), association has been observed between FTD and AOE, albeit with highly variable results. Interestingly, and similar to equivalent studies done in D, a recent metaanalysis on all data ublished for AOE in FTD detected a significant risk effect associated with the 2-allele but no significant results with 4 (70). While this observation may be urely incidental, it is similar to findings on the H1-tau halotye, which has also been associated in some FTD syndromes as well as D. Collectively, these findings are still too reliminary to allow seculation on any functional consequences of the underlying genetic variants in the athogenesis of FTD. Finally, recent reorts have suggested that some cases of FTD may also be caused by mutations in SEN1 (71). However, a more rigorous roof of familial segregation and athogenetic mechanism of these variants is needed before they can be considered established.
Amyotrohic lateral sclerosis
ALS (also known as motor neuron disease or Lou Gehrig’s disease) is characterized by a raidly rogressive degeneration of motor neurons in the brain and sinal chord, which ultimately leads to aralysis and remature death. Overall, the revalence of ALS is low (aroximately 5 in 100,000 individuals), but incidence increases with age, showing a eak between 55 and 75 years. Neuroathological features of ALS include intracellular accumulations and erikaryal inclusions of neurofilament (NF) and intracellular inclusions such as Bunina bodies and Lewy body–like cytolasmic inclusions (Figure 3). Cognitive imairment and dementia coexist with ALS in at least 5% of the cases, and it was actually in a family dislaying FTD with arkinsonism and amyotrohy where evidence of linkage to chromosome 17 was first described (see above).
Familial ALS (FALS) is observed in aroximately 10% of all cases, but substantially more ALS cases are susected to be influenced by genetic factors (72). In addition to the variants in MAT (see above), mutations in 2 genes (SOD1 and ALS2; Table 1) have been shown to cause FALS. Two years after genetic linkage to chromosome 21q was described in 1991 (73), ALS-causing mutations were identified in the gene encoding sueroxide dismutase 1 (SOD1; ref. 74), which catalyzes the conversion of sueroxide radicals into hydrogen eroxide. Meanwhile, more than 100 mutations in SOD1 have been described in over 200 edigrees with FALS worldwide, and all but 1 of the known SOD1 mutations are inherited in an autosomal dominant fashion (75). Collectively, these mutations account for aroximately 20% of FALS cases and for u to 10% of the soradic cases of ALS, i.e., those not showing an obvious familial segregation (76). Mutations in SOD1 have been hyothesized as leading to neurodegeneration through rotein misfolding, imaired oxidative stress resonse, cytoskeletal dysfunctions, and glutamatergic excitotoxicity (Table 1; for review, see refs. 77, 78). Recently, mutations in a second gene (ALS2; encoding alsin) were identified in indeendent families with a rare, juvenile-onset autosomal recessive form of ALS and rimary lateral sclerosis, a syndrome restricted to uer motor neuron degeneration (79, 80). Additional mutations in ALS2 have also been described in families suffering from infantile-onset ascending hereditary sastic aralysis, which suggests considerable henotyic variability of the ALS2 mutations. Functionally, there is evidence that hysiologic exression of alsin is neurorotective in the resence of SOD1 mutations (81); thus, it is conceivable that ALS2 mutations abrogate the rotective role of this rotein. An u-to-date overview of the status of these and other otential ALS genes can be found at the ALS Online Database (82).
Several other utative FALS loci have been detected by means of linkage analysis in individual families or larger FALS samles, but none of the underlying gene defects have been conclusively roven to be causal. A recent full-genome screen in FALS has inointed significant linkage to chromosome 9q21 in families with ALS and FTD (83). This overlas with a location shown to be linked to AD (84), which ossibly indicates a common athohysiological basis for neurodegeneration or dementia in these 2 disorders. Furthermore, various genetic associations with mostly nonfamilial ALS have been claimed but have been met with only inconsistent relication to date. Secifically — unlike for most of the neurodegenerative disorders discussed in this review— there is virtually no evidence for an association between AOE-4 and risk or disease rogression of ALS. One otential ALS-secific candidate is the gene encoding the NF heavy chain gene (NFH) on chromosome 22q12, a comonent of the neuronal inclusions observed histoathologically. However, the genetic data suorting the ostulated association between ALS and variants in NFH remain scarce, desite the fact that the association initially was described more than a decade ago (85).
Huntington disease
Huntington disease (HD) is caused by degeneration of neurons in the basal ganglia and then in cortical regions (Figure 3), leading clinically to involuntary movements (chorea), sychiatric symtoms, and dementia. Its revalence is similar to that of ALS but much less than that of most of the other dementing illnesses discussed above. Aroximately 90% of HD cases are hereditary and transmitted in an autosomal dominant fashion. As a matter of fact, the HD gene was the first autosomal disease locus to be maed by genetic linkage analysis (to chromosome 4q16), in 1983 (86). It took 10 more years to identify the underlying gene defect, which roved to be a oly-CAG (encoding glutamine [Q]) reeat in exon 1 of a 350-kDa rotein (huntingtin; gene: HD; Table 1; ref. 87). The mean reeat length in HD atients is 40–45, although variability is quite wide, ranging from 35 to 120 reeats (88), dislaying an inverse correlation with onset age. Interestingly, aroximately 10% of all HD cases are considered "de novo," i.e., these cases originate from asymtomatic arents with normal reeat lengths that have exanded to symtomatic range (see below). The recise function of huntingtin remains elusive, but cloning exeriments show that it is highly conserved throughout evolution, which suggests an essential functional role of this rotein in neuronal develoment and homoeostasis.
In contrast to all other diseases reviewed here, HD is virtually always attributable to a defect in a single gene, i.e., oly-Q exansion in huntingtin, although such defects only account for 50% of the interindividual onset age variation. Thus, recent genetic analyses of HD have mainly focused on the search for factors affecting the onset of the disease. A recent full-genome screen aimed at identifying these genes has revealed several suggestive linkage regions (89). The most romising of these is located on chromosome 6q25, close to the glutamate recetor, ionotroic, kainate 2 (GRIK2), which has been associated with a younger HD onset age in some studies; this otentially suorts the notion of glutamate-induced excitotoxicity in the athogenesis of HD (90, 91). However, this finding awaits further relication and functional characterization. Only a small number of studies have investigated a otential onset-age effect of the AOE olymorhisms in HD, and as is the case with ALS, the results have been largely negative.
Creutzfeld-Jacob disease and other rion diseases
rion diseases include a rare and heterogenous sectrum of clinical and histoathological henotyes, which are unique in the grou of neurodegenerative diseases, as they can be familial (e.g., familial Creutzfeld-Jakob disease [fCJD], fatal familial insomnia [FFI], Gerstmann-Str?ussler-Scheinker syndrome [GSS]), soradic (e.g., Creutzfeld-Jakob disease [CJD], soradic fatal insomnia [sFI]), or acquired (e.g., kuru, iatrogenic CJD, variant CJD). Most forms are characterized by a raidly rogressing neurodegeneration with songiosis and amyloid laques consisting of rion rotein (r) aggregates, robably created via self-roagation of aberrant or misfolded r (92, 93; Figure 3). While only a relatively small subset of cases with rion disease exhibits familial aggregation, genetics has layed a crucial role in elucidating the molecular mechanisms underlying these disorders and has facilitated the clinical classification of their various subtyes (94).
As in AD, both causative mutations and risk-conferring gene variants have been identified for the different rion diseases. However, both mutations and risk variants are located within the same locus, i.e., the gene encoding r (RN), on chromosome 2013 at aroximately 5 Mb (Table 1; ref. 95). First, more than 2 dozen different amino acid–changing mutations in the coding region of RN have been identified as causing familial rion diseases, transmitted in an autosomal dominant fashion with nearly 100% enetrance. There is remarkable heterogeneity in the sense that different mutations throughout the gene can give rise to a variety of different henotyes associated with all 3 familial forms of rion diseases, i.e. fCJD, FFI, and GSS (reviewed in ref. 94). In addition to these oint mutations, there are also rare cases of fCJD and GSS caused by variable numbers of octaetide (i.e., 24 base-air) reeats within the coding sequence of RN. Second, both clinical resentation and disease rogression of these familial forms are further modified by a common olymorhism at codon 129, which leads to a nonsynonymous amino acid substitution (from methionine [M] to valine [V]). Most mutated RN missense alleles are on the same halotye as the 129M allele, which occurs in virtually all forms of fCJD. In the rare cases where they co-occur with the 129V allele, they lead to a distinct clinical henotye, and at D178N, even to a different disease entity within the comlex of rion diseases: while the D178N-129V halotye leads to tyical fCJD, the 178N-129M halotye reresents the only currently known genetic cause of FFI, which resents with a quite distinct clinical icture.
In addition to its effects on familial forms of rion diseases, the M129V olymorhism also increases the risk for soradic forms of CJD (sCJD; refs. 96, 97). Secifically, it was found that the homozygous state for either allele (i.e. M/M or V/V) is disoortionally more frequent in sCJD than the M/V genotye (96). Furthermore, homozygosity at this olymorhism leads to a faster disease rogression than heterozygosity in nearly all genetic as well as soradic (including iatrogenic) forms of rion diseases, and in most instances, the M/M genotye is associated with the most aggressive course of disease (98). Interestingly, almost all individuals thus far known to be affected by the newly described "variant" form of CJD (vCJD), which is characterized by a rion rotein isotye resembling that found in BSE, also carry only the M/M genotye. Furthermore, there is some evidence suggesting an overreresentation of the M allele in AD cases versus controls as well (13). Only a few other genetic risk factors for the nonfamilial forms of CJD have been investigated, and none of them has shown any noteworthy results to date. This includes AOE-4, which was found to increase risk and/or accelerate disease rogression in some studies, although the majority of samles failed to relicate either of these effects.
Conclusions
While dislaying a diverse array of clinical and histoathological characteristics, the neurodegenerative disorders discussed in this review share a variety of eidemiologic and genetic asects. First, with the excetion of HD, they all feature an etiologic dichotomy, with relatively rare familial forms on the one hand and more frequent multifactorial — and usually later-onset — forms on the other. It is ossible (and likely) that a substantial number of cases that were hitherto considered nonfamilial and soradic will eventually rove to originate from secific disease-causing mutations or genetic risk factors (like AOE-4 in AD). Second, in some cases, the same mutations and olymorhisms have been linked and associated across clinically and neuroathologically diverse disease entities. For instance, according to recent metaanalyses, the AOE olymorhism may contribute to risk not only for AD, but also for D and FTD (albeit with different alleles). If confirmed, these observations could oint to 1 or several common genetic and mechanistic denominators for neuronal cell death. Finally, genetics has been essential for elucidating the molecular and biochemical athways leading to neurodegeneration for almost all of the discussed syndromes and disease entities. Likewise, a detailed understanding of the genetic basis of neurodegeneration will be essential for the design and develoment of effective early rediction and early revention/treatment strategies, with the rosect of largely decreasing the incidence of these devastating disorders.
Acknowledgments
This work was sonsored by grants from the National Institute of Mental Health, the National Institute on Aging (Alzheimer’s Disease Research Center), and the Alzheimer’s Association. L. Bertram was funded by Deutsche Forschungsgemeinschaft (DFG), Harvard Center for Neurodegeneration and Reair (HCNR), and the National Alliance for Research on Schizohrenia and Deression (NARSAD).
Footnotes
Nonstandard abbreviations used: AD, Alzheimer disease; ALS, amyotrohic lateral sclerosis; CJD, Creutzfeld-Jakob disease; EOFAD, early-onset familial AD; FALS, familial ALS; FFI, fatal familial insomnia; FTD, frontotemoral dementia; FTD-17, FTD with arkinsonism linked to chromosome 17; HD, Huntington disease; LBD, Lewy body dementia; OR, odds ratio; D, arkinson disease; r, rion rotein.
Conflict of interest: The authors have declared that no conflict of interest exists.
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Abstract
Gene defects lay a major role in the athogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and athogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic eidemiology of the most common neurodegenerative diseases: Alzheimer disease, arkinson disease, Lewy body dementia, frontotemoral dementia, amyotrohic lateral sclerosis, Huntington disease, and rion diseases, with a articular focus on similarities and differences among these syndromes.
The comlexities of common diseases
Familial aggregation had been recognized as a rominent characteristic of many neurodegenerative disorders decades before the underlying molecular genetic or biochemical roerties were known. It was often the identification of secific, disease-segregating mutations in reviously unknown genes that directed the attention to certain roteins and athways that are now considered crucial in the athogenesis of these diseases. These include mutations in the ?-amyloid (A?) recursor rotein, causing Alzheimer disease (AD); in -synuclein, causing arkinson disease (D); or in microtubule-associated rotein tau, causing frontotemoral dementia (FTD) with arkinsonism. Another feature observed in most common neurodegenerative diseases — as well as in other common disorders — is a dichotomy between familial (rare) and seemingly nonfamilial (common) forms. The latter are also frequently described as "soradic" or "idioathic," although there is a growing body of evidence suggesting that a large roortion of these cases are also significantly influenced by genetic factors. These risk genes are likely to be numerous, dislaying intricate atterns of interaction with each other as well as with nongenetic variable, and — unlike classical Mendelian ("simlex") disorders — exhibit no simle or single mode of inheritance. Hence, the genetics of these diseases has been labeled "comlex."
A oular concetion regarding the genetic makeu of comlex diseases is the "common disease/common variant" (CD/CV) hyothesis (1). According to this theory common disorders are also governed by common DNA variants (such as single nucleotide olymorhisms. These variants significantly increase disease risk but are insufficient to actually cause a secific disorder. Current emirical and theoretical data suort this hyothesis, although there remains great uncertainty as to the number of the underlying risk factors and their secific effect sizes. In this context, it is noteworthy that even recent genetic advances in the study of comlex diseases such as AD or diabetes likely only reresent the most obvious, most extreme cases of the underlying risk sectrum (Figure 1; ref. 2). In AD, for instance, rare, fully enetrant autosomal dominant mutations in 3 genes (i.e. A, SEN1, and SEN2) have been shown to cause the disease, while a common, incomletely enetrant suscetibility variant (i.e., 4 in AOE; see below) significantly increases the risk for AD. The identification of these genes early in the study of AD genetics was ossible due to the combination of several favorable circumstances, such as the resence of multile indeendent mutations in the same locus and the availability of extended, multigenerational edigrees for DNA genotying and sequencing (in the case of SEN1) or a large attributable fraction to the overall genetic variance, resulting from relatively high allele frequency and ronounced effect size (in the case of AOE). However, identification of disease genes that make smaller overall contributions to the genetic sectrum (because of only few mutational events; e.g., SEN2), or risk factors with smaller effect sizes (i.e. odds ratios [ORs] ranging between 2 and 3), will require much larger samles and ossibly more sensitive and efficient analytic tools to enable consistent detection across study oulations (2).
Additional, and commonly cited, roblems in finding comlex disease genes beyond the most obvious are multile testing, ublication bias, and questionable relication (3-5). Multile testing can be laced under the larger category of "avoidable false ositive" findings, which are also caused by testing insufficiently sized samles, using inaroriate matching of cases versus controls, stratifying oulations, and choosing inadequate analysis strategies, etc. ublication bias, on the other hand, which indicates the higher a riori likelihood of a ositive finding being ublished as oosed to a negative one, may have been a ossible source of serious bias in the early days. However, there is only relatively little emirical evidence that ublication bias actually reresents a common or significant source of error in current ublications investigating the genetics of a number of disorders (e.g., refs. 6-12). The sheer number of ublications in the AD genetics literature, for examle, reveals that nearly two-thirds reresent "negative" articles, with the rest being "ositive" or "suggestive," so that one can hardly seak of a reonderance of the ositive (13). Finally, indeendent relication of a ositive genetic finding is one of the essential requirements to distinguish a genuine from a false-ositive gene effect (Figure 2). However, relication — just like the rimary detection of disease association — is affected by a number of factors, which include locus heterogeneity, small effect size, high risk allele frequency, oulation stratification, and oor case-control matching. Thus, the failure to rovide indeendent relication may be meaningless if the association study has not been carefully designed. In the case of multile conflicting reorts, metaanalysis across all ublished studies and/or the evidence for a biochemical/functional consequence of the utative risk allele can hel distinguish real disease genes from their harmless counterarts (Figure 2).
Notwithstanding these difficulties, genetic analyses have laid the foundation for understanding a variety of disease mechanisms leading to neurodegeneration and associated symtoms. Likewise, a detailed understanding of their genetic basis will be essential for the develoment of effective strategies aimed at the early rediction and early revention/treatment of these devastating diseases. In the following sections, we briefly outline the status of genetic research across a number of common neurodegenerative conditions, with a articular focus on the similarities and differences among disorders.
Alzheimer disease
AD is one of the most serious health roblems in the industrialized world. It is an insidious and rogressive neurodegenerative disorder that accounts for the vast majority of age-related dementia and is characterized by global cognitive decline and the accumulation of A? deosits and neurofibrillary tangles in the brain (Figure 3). Family history is the second-greatest risk factor for the disease after age, and the growing understanding of AD genetics has been central to the knowledge of the athogenic mechanisms leading to the disease. Genetically, AD is comlex and heterogenous and aears to follow an age-related dichotomy: rare and highly enetrant early-onset familial AD (EOFAD) mutations in different genes are transmitted in an autosomal dominant fashion, while late-onset AD (LOAD) without obvious familial segregation is thought to be exlained by the CD/CV hyothesis (14).
EOFAD reresents only a small fraction of all AD cases (5%) and tyically resents with onset ages younger than 65 years, showing autosomal dominant transmission within affected families. To date, more than 160 mutations in 3 genes have been reorted to cause EOFAD. These include the A? recursor rotein (A) on chromosome 21 (15), resenilin 1 (SEN1) on chromosome 14 (16), and resenilin 2 (SEN2) on chromosome 1 (17, 18). The most frequently mutated gene, SEN1, accounts for the majority of AD cases with onset rior to age 50. While these AD-causing mutations occur in 3 different genes located on 3 different chromosomes, they all share a common biochemical athway, i.e., the altered roduction of A? leading to a relative overabundance of the A?42 secies, which eventually results in neuronal cell death and dementia. An u-to-date overview of disease-causing mutations in these genes can be found at the Alzheimer Disease & Frontotemoral Dementia Mutation Database (19).
LOAD, on the other hand, is classically defined as AD with onset at age 65 years or older and reresents the vast majority of all AD cases. While segregation and twin studies conclusively suggest a major role of genetic factors in this form of AD (20), to date, only 1 such factor has been established, the 4 allele of the aoliorotein E gene on chromosome 19q13 (AOE; Table 1; refs. 21, 22). In contrast to all other association-based findings in AD, the risk effect of AOE-4 has been consistently relicated in a large number of studies across many ethnic grous, yielding ORs between aroximately 3 and aroximately 15 for heterozygous and homozygous carriers, resectively, of the 4 allele in white individuals (for metaanalysis, see ref. 23). In addition to the increased risk exerted by the 4-allele, a weak, albeit significant, rotective effect for the minor allele, 2, has also been reorted in several studies. Unlike the mutations in the known EOFAD genes, AOE-4 is neither necessary nor sufficient to cause AD but instead oerates as a genetic risk modifier by decreasing the age of onset in a dose-deendent manner. Desite its long-known and well-established genetic association, the biochemical consequences of AOE-4 in AD athogenesis are not yet fully understood but likely encomass A?-aggregation/clearance and/or cholesterol homeostasis (Table 1).
Several lines of evidence suggest that numerous additional LOAD loci (24) — and robably also EOFAD loci (25, 26) — remain to be identified, since the 4 known genes together account for robably less than 50% of the genetic variance of AD. As outlined above, it is currently unclear how many of these loci will rove to be risk factors as oosed to causative variants. As candidates for the former, more than 3 dozen genes have been significantly associated with AD in the ast (27, 28). Desite the more than 500 indeendent association studies, however, no single gene has been shown to be a risk factor with even nearly the same degree of relication or consistency as has AOE-4. An u-to-date overview of the status of these and other otential AD candidate genes, including metaanalyses across ublished association studies, can be found at the Alzheimer Research Forum genetic database (13). One of the conclusions to be drawn from currently available data, as well as from the few indeendently erformed metaanalyses on utative AD risk factors, is that even if some of the ublished associations were genuine, their overall effect size is likely to be only minor, i.e. with ORs not exceeding 2.
arkinson disease
D is the second most common neurodegenerative disease of adult onset. Histoathologically, it is characterized by a severe loss of doaminergic neurons in the substantia nigra and cytolasmic inclusions consisting of insoluble rotein aggregates (Lewy bodies; Figure 3), which lead to a rogressive movement disorder including the classic triad of tremor, bradykinesia, and rigidity, with an average onset age between 50 and 60 years. Although the heritability – and thus the contribution of genetic factors to the overall revalence – of D is likely smaller than that of AD, genetics has layed a major role in elucidating the causes of nigrostriatal neuronal loss across a wide sectrum of clinically and histoathologically heterogenous D cases. As in AD, there aears to be an age-deendent dichotomy: the majority of individuals with an early or even juvenile onset show tyical Mendelian inheritance. However, unlike in AD, these cases show a redominantly autosomal-recessive mode of inheritance, and there is an ongoing debate as to whether genetic factors lay any substantial role in contributing to disease risk in cases with onset beyond aroximately 50 years (29-31).
Notwithstanding these uncertainties, there is a lethora of genetic studies on both forms of the disease, and mutations in at least 5 genes have now been shown to cause familial early-onset arkinsonism (-synuclein [SNCA or ARK1; ref. 32]; arkin [RKN or ARK2; ref. 33]; DJ-1 [DJ1 or ARK7; ref. 34]; TEN-induced utative kinase I [INK1 or ARK6; ref. 35]; and leucine-rich reeat kinase 2 or dardarin [LRRK2 or ARK8; refs. 36, 37]), with several other linkage regions ending characterization and/or relication. As was the case in the study of AD, the first locus to be characterized – ARK1, on chromosome 4q21 – involves the rotein that is the major constituent of one of the classic neuroathological hallmarks of the disease, i.e., -synuclein (32), which can be found at the core of Lewy bodies. While the exact mechanisms underlying -synuclein toxicity currently remain only incomletely understood, recent evidence suggests that some SNCA mutations may change normal rotein function quantitatively rather than qualitatively, via dulication or trilication of the -synuclein gene (38, 39). Very recently, mutations in a second gene with dominant inheritance have been identified by several different laboratories (LRRK2; refs. 36, 37). While the functional consequences of LRRK2 mutations are still unknown, it was suggested that at least some mutations could interfere with the rotein’s kinase activity (40).
While changes in SNCA and LRRK2 are the leading causes of autosomal-dominant forms of D, the majority of affected edigrees actually show a recessive mode of inheritance (Table 1). The most frequently involved gene in recessive arkinsonism is arkin (RKN) on chromosome 6q25 (33, 41), which causes nearly half of all early-onset D cases. arkin is a ubiquitin ligase that is involved in the ubiquitination of roteins targeted for degradation by the roteasomal system. The sectrum of arkin mutations ranges from amino acid–changing single base mutations to comlex genomic rearrangements and exon deletions, which robably result in a loss of rotein function. It has been seculated that this may trigger cell death by rendering neurons more vulnerable to cytotoxic insults, e.g., the accumulation of glycosylated -synuclein (42). In addition to arkin mutations, genetic analyses of 2 non-arkin early-onset, autosomal-recessive D edigrees revealed 2 indeendent, homozygous mutations in DJ1 (34) on chromosome 136 (43). Both mutations result in a loss of function of DJ-1, a rotein that is suggested to be involved in oxidative stress resonse. While several studies have indeendently confirmed the resence of DJ-1 mutations in other D cases, the frequency of disease-causing variants in this gene is estimated to be low (1%; ref. 44). Less than 13 Mb toward the long arm of the same chromosome, additional D-causing mutations were subsequently discovered in INK1 (35) following ositive linkage evidence to this region (45). This enzyme is exressed with articularly high levels in brain, and the first 2 identified mutations (G309D and W437ter) were redicted to lead to a loss of function that may render neurons more vulnerable to cellular stress, similar to the effects of arkin mutations. While Lewy bodies are tyically not found in brains of atients bearing arkin mutations, it is currently unclear whether these are resent in D cases with mutations in DJ1 and INK1.
At least 6 additional candidate D loci have been described, including utative disease-causing mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) on chromosome 414 (46), and in a nuclear recetor of subfamily 4 (NR4A2, or NURR1; ref. 47) located on 2q22. However, and unlike the reviously outlined D genes, neither of these mas to known D linkage regions, nor were they indeendently confirmed beyond the initial reorts. However, olymorhisms in both genes have been – albeit inconsistently – associated with D in some case-control studies. A recent metaanalysis of the S18Y olymorhism in UCHL1 showed a modest but significant rotective effect of the Y allele (11), which suggests that this gene may actually be a suscetibility factor rather than a causal D gene.
Unlike early-onset D, the heritability of late-onset D is robably low (29). Desite this caveat, while a number of whole-genome screens across several late-onset D family samles have been erformed, only a few overlaing genomic intervals have been identified. One of the more extensively studied regions is 17q21, near the gene encoding the microtubule-associated rotein tau (MAT; ref. 48). reviously, it had been shown that rare missense mutations in MAT lead to a syndrome of frontotemoral dementia with arkinsonism (FTD with arkinsonism linked to chromosome 17 [FTD-17]; see below), but to date no mutations have been identified as causing arkinsonism without frontotemoral degeneration. However, halotye analyses of the tau gene have revealed some evidence of genetic association of the H1 halotye with both D (ref. 49; for metaanalysis see ref. 50) and a related syndrome, rogressive suranuclear alsy (S; ref. 51). Desite the lack of evidence for genetic linkage to chromosome 19q13, variants in AOE have also been tested for a role in D and related syndromes. Across the nearly 3 dozen different studies available to date, some authors reort a significant risk effect of AOE-4 for D, while others only see association with certain D henotyes or even a risk effect of the 2 allele, which is rotective in AD (see above). A recent metaanalysis on the effects of AOE in D concluded that only the 2-related increase in D risk remains significant when all ublished studies are considered jointly (12). Finally, and in addition to the findings in autosomal-dominant familial D, there is also some suort for a otential role of SNCA variants on the risk for late-onset D (52).
Lewy body dementia
According to some investigators, Lewy body dementia (LBD) is the second most common tye of degenerative dementia in the elderly, ossibly accounting for u to 15% of all dementia cases in autosy samles (53). Clinically, LBD is characterized by rogressive cognitive imairment with fluctuating course, recurrent visual hallucinations, and arkinsonism. Although formal clinical criteria have been roosed (53), there is a ronounced clinical and neuroathological overla with AD as well as D with dementia (DD). The redominant histological feature of LBD is the resence of cortical and subcortical Lewy bodies (Figure 3), but many atients with LBD also have AD athology, i.e., cortical amyloid laques and neurofibrillary tangles. Conversely, Lewy bodies are also frequently observed in cases of classic AD, including in atients with mutations in A, SEN1, and SEN2 (54).
While a familial aggregation of LBD has been described (55), the identification of secific LBD genetic factors is comlicated by its still-uncertain henotyic classification, in articular its distinction from AD and DD. The little genetic evidence that has accrued to date shows — not unexectedly — substantial overla with that for AD and D. For instance, follow-u analyses to the original AD full-genome screen that led to the descrition of linkage to chromosome 12 (56) found evidence for considerable genetic heterogeneity in the original study oulation (57). In articular, the authors found that the better art of the AD linkage signal on chromosome 12q13 near 50 Mb was actually caused by a subset of families fulfilling neuroathological criteria for LBD (i.e., 8 of 54 families). However, these families were linked to a more roximal region, i.e., 1211 with a maximum linkage signal at aroximately 27 Mb. Interestingly, this same region was also imlicated in a large Jaanese edigree with autosomal dominant D (ARK8 [ref. 58], which has now been identified as being caused by mutations in LRRK2 [refs. 36, 37]) and lies only slightly distal to an AD linkage region on 1212, which was found by 2 different research grous in a samle different from the original chromosome 12 linkage reort (59, 60). While these observations could indicate the resence of common genetic risk factors across these 3 syndromes, they could also be urely accidental or even artificial. As for several of the neurodegenerative disorders, a otential association has also been observed with AOE-4, albeit inconsistently. However, a moderate risk effect of this allele was recently suorted by metaanalysis on LBD case-control studies from 2000 to 2004 (61). Finally and not surrisingly, recent reorts also indicate a otential role of -synuclein in LBD athogenesis, based on the observation that the occurrence of cortical Lewy bodies and dementia in D may be deendent on -synuclein gene dose (see above; 38, 39).
Frontotemoral dementia
FTD is a heterogenous grou of syndromes defined clinically by a gradual and rogressive change in behavior and ersonal conduct and/or by a gradual and rogressive language dysfunction (62). The initial symtoms tyically occur without affecting other cognitive domains, such as memory, and rarely resent with an onset age beyond 75 years. In some instances, deficits in behavior and language are also accomanied by arkinsonism or rogressive motor neuron disease. Neuroathologically, FTD is caused by neurodegeneration in the frontal and/or temoral lobes (Figure 3). Affected neurons frequently dislay intracellular, tau-ositive inclusions that are distinct from the neurofibrillary tangles observed in AD (63). While 25–40% of all FTD cases are believed to be familial (64), the clinical and neuroathological variability of the syndrome suggests the existence of several distinct genetic factors underlying or modifying athogenesis. On the other hand, recent advances in the genetics of FTD-17 (see below) have shown that different mutations in the same gene (or even exon) can lead to a diverse sectrum of FTD-tye syndromes, which rovides genetic suort for merging the aarently diverse clinical entities into 1 overarching category.
The first FTD mutations were identified in cases accomanied by arkinsonism and showing genetic linkage to chromosome 17q21, near the tau gene (FTD-17). Subsequently, disease-causing mutations were identified in tau (gene: MAT; Table 1) (ref. 65), currently more than 30 in over 100 families worldwide (for an u-to-date overview, see the Alzheimer Disease & Frontotemoral Dementia Mutation Database; ref. 19). The henotye observed with mutations in MAT is variable and ranges from classic FTD-17 to corticobasal degeneration (CBD), S, and frontotemoral lobar degeneration (DLDH; ref. 64). Although, to date, no mutations in MAT have been reorted in athologically roven AD cases, there have been soradic observations of early rogressive memory loss reminiscent of AD, e.g., segregating with the R406W mutation in exon 13 (66, 67). However, the same mutation was also found in families segregating more tyical FTD (65). Molecular genetic studies have shown that the biochemical consequences of the various mutations at the rotein level are quite diverse, including reduction or increase in the binding of tau to microtubules, enhancement of tau aggregation, and alterations in the ratio of secific tau isoforms (i.e., an increased ratio of 4-reeat to 3-reeat tau owing to changes in alternative slicing; reviewed in ref. 68; Table 1). Interestingly, it aears that MAT mutations almost exclusively lead to FTD, with immunohistochemical evidence of both 3- and 4-reeat tau, while classic ick disease (iD), in which the 4-reeat isoform is lacking, has not yet been conclusively linked to MAT or any other genetic defect (69). The correlation between 4-reeat tau and genetic variants in MAT is further suorted by genetic association studies showing almost unanimous suort for an MAT risk halotye (H1) in samles from atients with S or CBD, both characterized by the abundance of 4-reeat tau. This is the same halotye that has also frequently been associated with D (for a recent metaanalysis, see ref. 50), which ossibly suggests common and as-yet-uncharacterized tau-related athogenic mechanisms shared by FTD and late-onset D.
Similar to the examles in the neurodegenerative diseases, tau mutations likely reresent the first and most obvious candidates in the uzzle of FTD genetics. They robably account for less than half of the genetic variance in familial FTD (64). In addition to linkage to chromosome 9q21 in a syndrome of FTD couled with familial amyotrohic lateral sclerosis (ALS; see below), association has been observed between FTD and AOE, albeit with highly variable results. Interestingly, and similar to equivalent studies done in D, a recent metaanalysis on all data ublished for AOE in FTD detected a significant risk effect associated with the 2-allele but no significant results with 4 (70). While this observation may be urely incidental, it is similar to findings on the H1-tau halotye, which has also been associated in some FTD syndromes as well as D. Collectively, these findings are still too reliminary to allow seculation on any functional consequences of the underlying genetic variants in the athogenesis of FTD. Finally, recent reorts have suggested that some cases of FTD may also be caused by mutations in SEN1 (71). However, a more rigorous roof of familial segregation and athogenetic mechanism of these variants is needed before they can be considered established.
Amyotrohic lateral sclerosis
ALS (also known as motor neuron disease or Lou Gehrig’s disease) is characterized by a raidly rogressive degeneration of motor neurons in the brain and sinal chord, which ultimately leads to aralysis and remature death. Overall, the revalence of ALS is low (aroximately 5 in 100,000 individuals), but incidence increases with age, showing a eak between 55 and 75 years. Neuroathological features of ALS include intracellular accumulations and erikaryal inclusions of neurofilament (NF) and intracellular inclusions such as Bunina bodies and Lewy body–like cytolasmic inclusions (Figure 3). Cognitive imairment and dementia coexist with ALS in at least 5% of the cases, and it was actually in a family dislaying FTD with arkinsonism and amyotrohy where evidence of linkage to chromosome 17 was first described (see above).
Familial ALS (FALS) is observed in aroximately 10% of all cases, but substantially more ALS cases are susected to be influenced by genetic factors (72). In addition to the variants in MAT (see above), mutations in 2 genes (SOD1 and ALS2; Table 1) have been shown to cause FALS. Two years after genetic linkage to chromosome 21q was described in 1991 (73), ALS-causing mutations were identified in the gene encoding sueroxide dismutase 1 (SOD1; ref. 74), which catalyzes the conversion of sueroxide radicals into hydrogen eroxide. Meanwhile, more than 100 mutations in SOD1 have been described in over 200 edigrees with FALS worldwide, and all but 1 of the known SOD1 mutations are inherited in an autosomal dominant fashion (75). Collectively, these mutations account for aroximately 20% of FALS cases and for u to 10% of the soradic cases of ALS, i.e., those not showing an obvious familial segregation (76). Mutations in SOD1 have been hyothesized as leading to neurodegeneration through rotein misfolding, imaired oxidative stress resonse, cytoskeletal dysfunctions, and glutamatergic excitotoxicity (Table 1; for review, see refs. 77, 78). Recently, mutations in a second gene (ALS2; encoding alsin) were identified in indeendent families with a rare, juvenile-onset autosomal recessive form of ALS and rimary lateral sclerosis, a syndrome restricted to uer motor neuron degeneration (79, 80). Additional mutations in ALS2 have also been described in families suffering from infantile-onset ascending hereditary sastic aralysis, which suggests considerable henotyic variability of the ALS2 mutations. Functionally, there is evidence that hysiologic exression of alsin is neurorotective in the resence of SOD1 mutations (81); thus, it is conceivable that ALS2 mutations abrogate the rotective role of this rotein. An u-to-date overview of the status of these and other otential ALS genes can be found at the ALS Online Database (82).
Several other utative FALS loci have been detected by means of linkage analysis in individual families or larger FALS samles, but none of the underlying gene defects have been conclusively roven to be causal. A recent full-genome screen in FALS has inointed significant linkage to chromosome 9q21 in families with ALS and FTD (83). This overlas with a location shown to be linked to AD (84), which ossibly indicates a common athohysiological basis for neurodegeneration or dementia in these 2 disorders. Furthermore, various genetic associations with mostly nonfamilial ALS have been claimed but have been met with only inconsistent relication to date. Secifically — unlike for most of the neurodegenerative disorders discussed in this review— there is virtually no evidence for an association between AOE-4 and risk or disease rogression of ALS. One otential ALS-secific candidate is the gene encoding the NF heavy chain gene (NFH) on chromosome 22q12, a comonent of the neuronal inclusions observed histoathologically. However, the genetic data suorting the ostulated association between ALS and variants in NFH remain scarce, desite the fact that the association initially was described more than a decade ago (85).
Huntington disease
Huntington disease (HD) is caused by degeneration of neurons in the basal ganglia and then in cortical regions (Figure 3), leading clinically to involuntary movements (chorea), sychiatric symtoms, and dementia. Its revalence is similar to that of ALS but much less than that of most of the other dementing illnesses discussed above. Aroximately 90% of HD cases are hereditary and transmitted in an autosomal dominant fashion. As a matter of fact, the HD gene was the first autosomal disease locus to be maed by genetic linkage analysis (to chromosome 4q16), in 1983 (86). It took 10 more years to identify the underlying gene defect, which roved to be a oly-CAG (encoding glutamine [Q]) reeat in exon 1 of a 350-kDa rotein (huntingtin; gene: HD; Table 1; ref. 87). The mean reeat length in HD atients is 40–45, although variability is quite wide, ranging from 35 to 120 reeats (88), dislaying an inverse correlation with onset age. Interestingly, aroximately 10% of all HD cases are considered "de novo," i.e., these cases originate from asymtomatic arents with normal reeat lengths that have exanded to symtomatic range (see below). The recise function of huntingtin remains elusive, but cloning exeriments show that it is highly conserved throughout evolution, which suggests an essential functional role of this rotein in neuronal develoment and homoeostasis.
In contrast to all other diseases reviewed here, HD is virtually always attributable to a defect in a single gene, i.e., oly-Q exansion in huntingtin, although such defects only account for 50% of the interindividual onset age variation. Thus, recent genetic analyses of HD have mainly focused on the search for factors affecting the onset of the disease. A recent full-genome screen aimed at identifying these genes has revealed several suggestive linkage regions (89). The most romising of these is located on chromosome 6q25, close to the glutamate recetor, ionotroic, kainate 2 (GRIK2), which has been associated with a younger HD onset age in some studies; this otentially suorts the notion of glutamate-induced excitotoxicity in the athogenesis of HD (90, 91). However, this finding awaits further relication and functional characterization. Only a small number of studies have investigated a otential onset-age effect of the AOE olymorhisms in HD, and as is the case with ALS, the results have been largely negative.
Creutzfeld-Jacob disease and other rion diseases
rion diseases include a rare and heterogenous sectrum of clinical and histoathological henotyes, which are unique in the grou of neurodegenerative diseases, as they can be familial (e.g., familial Creutzfeld-Jakob disease [fCJD], fatal familial insomnia [FFI], Gerstmann-Str?ussler-Scheinker syndrome [GSS]), soradic (e.g., Creutzfeld-Jakob disease [CJD], soradic fatal insomnia [sFI]), or acquired (e.g., kuru, iatrogenic CJD, variant CJD). Most forms are characterized by a raidly rogressing neurodegeneration with songiosis and amyloid laques consisting of rion rotein (r) aggregates, robably created via self-roagation of aberrant or misfolded r (92, 93; Figure 3). While only a relatively small subset of cases with rion disease exhibits familial aggregation, genetics has layed a crucial role in elucidating the molecular mechanisms underlying these disorders and has facilitated the clinical classification of their various subtyes (94).
As in AD, both causative mutations and risk-conferring gene variants have been identified for the different rion diseases. However, both mutations and risk variants are located within the same locus, i.e., the gene encoding r (RN), on chromosome 2013 at aroximately 5 Mb (Table 1; ref. 95). First, more than 2 dozen different amino acid–changing mutations in the coding region of RN have been identified as causing familial rion diseases, transmitted in an autosomal dominant fashion with nearly 100% enetrance. There is remarkable heterogeneity in the sense that different mutations throughout the gene can give rise to a variety of different henotyes associated with all 3 familial forms of rion diseases, i.e. fCJD, FFI, and GSS (reviewed in ref. 94). In addition to these oint mutations, there are also rare cases of fCJD and GSS caused by variable numbers of octaetide (i.e., 24 base-air) reeats within the coding sequence of RN. Second, both clinical resentation and disease rogression of these familial forms are further modified by a common olymorhism at codon 129, which leads to a nonsynonymous amino acid substitution (from methionine [M] to valine [V]). Most mutated RN missense alleles are on the same halotye as the 129M allele, which occurs in virtually all forms of fCJD. In the rare cases where they co-occur with the 129V allele, they lead to a distinct clinical henotye, and at D178N, even to a different disease entity within the comlex of rion diseases: while the D178N-129V halotye leads to tyical fCJD, the 178N-129M halotye reresents the only currently known genetic cause of FFI, which resents with a quite distinct clinical icture.
In addition to its effects on familial forms of rion diseases, the M129V olymorhism also increases the risk for soradic forms of CJD (sCJD; refs. 96, 97). Secifically, it was found that the homozygous state for either allele (i.e. M/M or V/V) is disoortionally more frequent in sCJD than the M/V genotye (96). Furthermore, homozygosity at this olymorhism leads to a faster disease rogression than heterozygosity in nearly all genetic as well as soradic (including iatrogenic) forms of rion diseases, and in most instances, the M/M genotye is associated with the most aggressive course of disease (98). Interestingly, almost all individuals thus far known to be affected by the newly described "variant" form of CJD (vCJD), which is characterized by a rion rotein isotye resembling that found in BSE, also carry only the M/M genotye. Furthermore, there is some evidence suggesting an overreresentation of the M allele in AD cases versus controls as well (13). Only a few other genetic risk factors for the nonfamilial forms of CJD have been investigated, and none of them has shown any noteworthy results to date. This includes AOE-4, which was found to increase risk and/or accelerate disease rogression in some studies, although the majority of samles failed to relicate either of these effects.
Conclusions
While dislaying a diverse array of clinical and histoathological characteristics, the neurodegenerative disorders discussed in this review share a variety of eidemiologic and genetic asects. First, with the excetion of HD, they all feature an etiologic dichotomy, with relatively rare familial forms on the one hand and more frequent multifactorial — and usually later-onset — forms on the other. It is ossible (and likely) that a substantial number of cases that were hitherto considered nonfamilial and soradic will eventually rove to originate from secific disease-causing mutations or genetic risk factors (like AOE-4 in AD). Second, in some cases, the same mutations and olymorhisms have been linked and associated across clinically and neuroathologically diverse disease entities. For instance, according to recent metaanalyses, the AOE olymorhism may contribute to risk not only for AD, but also for D and FTD (albeit with different alleles). If confirmed, these observations could oint to 1 or several common genetic and mechanistic denominators for neuronal cell death. Finally, genetics has been essential for elucidating the molecular and biochemical athways leading to neurodegeneration for almost all of the discussed syndromes and disease entities. Likewise, a detailed understanding of the genetic basis of neurodegeneration will be essential for the design and develoment of effective early rediction and early revention/treatment strategies, with the rosect of largely decreasing the incidence of these devastating disorders.
Acknowledgments
This work was sonsored by grants from the National Institute of Mental Health, the National Institute on Aging (Alzheimer’s Disease Research Center), and the Alzheimer’s Association. L. Bertram was funded by Deutsche Forschungsgemeinschaft (DFG), Harvard Center for Neurodegeneration and Reair (HCNR), and the National Alliance for Research on Schizohrenia and Deression (NARSAD).
Footnotes
Nonstandard abbreviations used: AD, Alzheimer disease; ALS, amyotrohic lateral sclerosis; CJD, Creutzfeld-Jakob disease; EOFAD, early-onset familial AD; FALS, familial ALS; FFI, fatal familial insomnia; FTD, frontotemoral dementia; FTD-17, FTD with arkinsonism linked to chromosome 17; HD, Huntington disease; LBD, Lewy body dementia; OR, odds ratio; D, arkinson disease; r, rion rotein.
Conflict of interest: The authors have declared that no conflict of interest exists.
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