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The genetics of disorders with synuclein pathology and parkinsonism
Introduction
The Genetics Of Synucleinopathies
Genetics of the diseases in which [alpha]-synuclein deposits are the predominant pathology
The genetics of the diseases in which [alpha]-synuclein is the secondary pathology
The genetics of the diseases with tau pathology
Summary, Synthesis And Speculation
Acknowledgements
References
The genetics of disorders with synuclein pathology and parkinsonism
Received May 26, 1999; Accepted June 1, 1999
Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of [alpha]-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.
INTRODUCTION
Parkinsonism is the term used to describe a constellation of clinical signs which includes resting tremor, rigidity, gait disturbance and postural instability, along with other `secondary' features. The most common form of parkinsonism is Parkinson's disease (PD). This disorder is pathologically characterized by the presence of Lewy bodies [intracellular inclusions staining with both [alpha]-synuclein and ubiquitin antibodies (1) in the brain stem], associated neuronal loss and notable depigmentation of the substantia nigra. Importantly, Lewy bodies are also found in other diseases, such as some Alzheimer's disease (AD) cases (2) and some prion diseases (3). As the eponym indicates, Lewy bodies are the hallmark pathological finding in Lewy body dementia (LBD) (4); whether this is a disease on one end of a spectrum of Lewy body diseases, including in its range PD and LBD, or is a distinct clinicopathological entity is the subject of current debate (discussed below). Synuclein abnormalities also occur in the parkinsonian disorder multiple system atrophy (MSA). In this disease there is abnormal oligodendroglial staining with synuclein antibodies, but no Lewy bodies (5). Parkinsonism is also a feature of other diseases that are characterized by the presence of neurofibrillary tangles (intracellular lesions consisting of the tau protein). These include: progressive supranuclear palsy (PSP) (6); bodig (Parkinson's dementia complex of Guam) (7); frontal-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (8). In addition, there are recessive disorders in which parkinsonism is a feature: these include `juvenile' parkinsonism (AR-JP, for which mutations in the parkin gene on chromosome 6 have been identified as responsible) (9); and lubag, an X-linked recessive parkinsonism-dystonia complex seen on the Philippine island of Panay (10). These latter are not reviewed herein.
The primary purpose of this article is to review recent progress in the genetics of those diseases in which synuclein pathology is a prominent feature. However, it is clear that both the etiology and clinical features overlap with those of diseases with tau pathology, so relevant recent information on these diseases will be briefly discussed.
THE GENETICS OF SYNUCLEINOPATHIES
[alpha]-Synuclein deposits occur in many diseases: they are the predominant lesions in PD, LBD and MSA, and they are the secondary lesion in AD and some cases of prion disease (Fig. 1). In PD, LBD and MSA the synuclein pathology is the predominant and possibly primary pathology, whereas in AD and the prion diseases the synuclein pathology is, we will argue, secondary to other lesions that lead to extracellular protein deposition.
Figure 1. Synuclein pathology in PD, LBD and MSA. (a) H&E staining of an interneuronal Lewy body in the substantia nigra of a patient with PD; (b) Lewy body stained with a polyclonal antibody to [alpha]-synuclein; (c) ubiquitin (rhodamine, red) and [alpha]-synuclein (FITC, green) antibodies showing co-staining of Lewy neurites in the frontal cortex (CA2/3) of a patient with LBD; (d) glial cytoplasmic inclusions stained with [alpha]-synuclein antibodies in MSA.
Genetics of the diseases in which [alpha]-synuclein deposits are the predominant pathology
PD and LBD.
PD was for many years considered the archetypal `non-genetic' disorder, however, a re-evaluation and meta-analysis of twin studies suggested that genetic factors had an important part to play (11). Cross-sectional surveys have shown that early onset PD (arbitrarily designated as <50 years) had a high genetic component, but late onset disease had a less evident component (12) (this issue is further discussed below). However, limited longitudinal evaluation of twins with late onset PD, by 18F-dopa positron emission tomography, suggests that cross-sectional studies are overlooking pre-symptomatic disease (13). In addition, several families in which apparently autosomal dominant disease has been well-documented (14-19) offer the classic route to the identification of pathogenic loci.
In 1996, Polymeropoulos and colleagues identified genetic linkage to Lewy body parkinsonism in the Contursi kindred (15,20). The [alpha]-synuclein gene had previously been mapped into the region defined by the linkage study (21). The following year they reported a mutation, A53T, which segregated with the disease in the family (22). This mutation has subsequently been identified in several other families, all of whom are of Greek or Southern Italian origin, suggesting a founder effect (22,23). A second mutation, A30P, has been described in a single family of German origin (24). Both [alpha]-synuclein mutations appear to be almost fully penetrant (22,23). The identification of these pathogenic mutations was particularly interesting and surprising for two reasons. First, because most species, including mouse, have a threonine at codon 53 and thus the pathogenic mutation can be thought of as a `revertant' (although there are other differences between the human and mouse sequence; 25). Second, because a fragment of [alpha]-synuclein (the non-amyloid component of plaques, NAC) was suggested to be part of the pathology of AD, although this has not been confirmed (26). The identification of [alpha]-synuclein as a gene for Lewy body parkinsonism led immediately to the realization that [alpha]-synuclein is a major component of Lewy bodies (27).
The normal function of [alpha]-synuclein is unknown (28); however, a role in synaptic transport of vesicles or in synaptic plasticity has been suggested (29). It is not known whether the pathogenic mutations inhibit this function (although there is some suggestion that they might; 29). However, in vitro data suggest that the mutant protein is more prone to fibrillogenesis (30-33). This has led to the idea that fibrillogenesis of the mutant protein is the key feature which leads to pathogenesis.
Most families multiply affected by Lewy body parkinsonism do not have a lesion in the [alpha]-synuclein gene (25). Two other loci have been reported for Lewy body parkinsonism: the first on chromosome 2p (34) and the second on chromosome 4p (35). These loci are not fully penetrant with respect to Lewy body parkinsonism; indeed, in both cases, it seems that only about half the gene carriers develop the disease (34,35). Furthermore, it is also clear that even these three loci together ([alpha]-synuclein, ch2p and ch4p) do not account for the majority of the familial cases of Lewy body parkinsonism. Thus, ironically, it seems likely that there will be at least four, and probably more, genetic loci for a disease that was considered `non-genetic'.
Multiple loci encoding the parkinsonian phenotype is one level of complexity in the genetics of this disorder, but the situation is, in fact, more complex than this in two related ways: first, the loci are non-penetrant; secondly, the neurodegenerative disease phenotype encompasses more than simple parkinsonism.
Non-penetrance of PD loci and the occurrence of essential tremor as an alternative phenotype.
All three genetic loci so far identified by linkage analysis are incompletely penetrant. Part of the biological reason for this is probably that loss of ~70% of nigral neurons is required for expression of the parkinsonian phenotype (36). Thus, individuals with a loss of neurons of less than this amount will appear unaffected. This is also, almost certainly, part of the reason why twin studies (which by their nature are largely cross-sectional) fail to show high degrees of concordancy in monozygotic twins (12; see ref. 13 for a discussion of this issue). However, the fact that PD is a disease with a distinct clinical threshold is not the whole explanation of non-penetrance since, in the ch4p-encoded family, the onset of disease is typically ~40 years with death at 50 years, yet unaffected haplotype carriers have a normal life expectancy (16,17,35). Thus, it seems likely that other factors, possibly also genetic, modify the expressivity of this locus. Interestingly, and related to this, most of the haplotype carriers of the ch4p locus who do not develop neurodegenerative disease have essential tremor. This is a relatively benign and non-progressive tremor clinically distinct from the resting tremor of PD (37). While this is a surprising finding, it is not unprecedented, in that essential tremor has frequently been reported to occur more frequently in the relatives of individuals with PD (38,39).
The relationship between PD and LBD: alternative phenotypes of the same process.
As discussed briefly above, PD is a distinctive clinical entity whose symptoms are largely dependent on the lesion of the substantia nigra. However, Lewy body degeneration occurs in other parts of the brain in PD. Furthermore, a proportion of individuals develop dementia in which their sole cortical pathology is the occurrence of Lewy bodies (4,40). From a clinical perspective, this syndrome, LBD, consists of progressive dementia as the core feature, with fluctuations in cognition, hallucinations and parkinsonism. Patients with LBD may be particularly prone to developing, or progressive severity of, parkinsonism, when exposed to neuroleptic medication and may be dramatically responsive to cholinesterase inhibitors. The relationship between LBD and PD is not clear, largely because the etiologies of both disorders individually are unclear. However, the family in which the ch4p locus segregates includes some individuals who fit the clinical criteria for PD and others who fit the criteria for LBD (17; unpublished data). Thus it is the authors' opinion that LBD and PD share the same etiology and pathogenic mechanisms and differ only in the neuronal populations affected by disease.
MSA.
MSA is a sporadic, late onset (typically 50-65 years) disease whose clinical presentation overlaps with PD, but in which autonomic failure is a pronounced feature and in which cerebellar signs such as ataxia may occur (41). It is characterized by neuronal loss and by the occurrence of oligodendroglial inclusions; these inclusions stain positive for [alpha]-synuclein (42). No risk factors, either genetic or environmental, have yet been identified for MSA.
The genetics of the diseases in which [alpha]-synuclein is the secondary pathology
A well-established observation has been the occurrence of Lewy bodies in individuals with neuritic plaques, often in the absence or near absence of the occurrence of neurofibrillary tangles (2). However, with the advent of molecular genetic analysis of families with AD, it has become clear that Lewy bodies occur in families with either amyloid precursor protein (APP) (43,44) or presenilin (44,45) mutations. This indicates that in this circumstance Lewy body/synuclein pathology is a consequence of the primary pathology in APP processing. This surprising observation has been extended to the prion diseases, in which, in those prion families in which neurofibrillary tangles were previously reported, the advent of synuclein antibodies has also revealed the occurrence of Lewy bodies (3,46). In addition, with respect to AD at least, it seems as if the tangle/tau pathology and the Lewy body/synuclein pathology are alternative responses to the primary lesion, because cases of AD with little tau pathology have much synuclein pathology and vice versa (47).
The genetics of the diseases with tau pathology
Neurofibrillary tangles are most frequently thought of in connection with AD, however, there is a long list of neurodegenerative diseases with parkinsonism and tangle pathology (48). Most notable are pathological data from chromosome 6q-linked juvenile onset parkinsonism (AR-JP) (9,49). While devoid of Lewy body inclusions, there is prominent neuronal loss in the substantia nigra and locus ceruleus with tau staining of neurofibrillary tangles in cerebral cortex and brainstem nuclei (50). The number of different mutations described in the parkin gene will ultimately provide insight into both the protein's function and resultant clinical and pathological presentations. Also of relevance to this review are FTDP-17 (51), in which the pathogenic mutations are within the tau gene (52,53), and PSP. Work on FTDP-17 and the relationship between this disease and AD has recently been reviewed (54,55). However, progress on the etiology of PSP has occurred since these reviews and will thus be discussed herein.
The genetics of PSP.
PSP is the second most common cause of parkinsonism (56). It is characterized by the occurrence of neurofibrillary tangles composed of straight filaments comprising almost entirely of tau in which the deposited protein contains four microtubule-binding repeats (57). In contrast, in AD both three and four repeat tau is deposited (54,55). Families with multiple cases of PSP have not been convincingly demonstrated and thus genetic factors were not thought to play a significant role in the pathogenesis of this disease. However, Saitoh and colleagues showed a robust association between homozygosity of a common allele at a dinucleotide repeat marker and PSP that has been multiply confirmed (58). Recently this association was shown to reflect the occurrence of common tau haplotypes that differ in gene structure, but not in protein coding sequence, and that homozygosity of the common allele (H1) predisposes to disease (59). It is not yet clear whether there has been a mutation on the H1 background that predisposes to disease or whether the H1 haplotype itself is a `low penetrance' risk factor locus with a recessive mode of inheritance. The absence of families with multiple cases of PSP would seem to provide evidence against the existence of a rare highly penetrant mutation that is associated with some versions of the H1 haplotype. The presence of neurofibrillary tangles in PSP that are made of four repeat tau indicates that, whatever the pathogenic process in this disease, it results in the selective deposition of these isoforms. This is similar to missense mutations and 5[prime] splice site mutations that affect exon 10 of the tau gene and which are associated with the development of FTDP-17. Thus the most parsimonious explanation of the genetic data in PSP is that the H1 haplotype prediposes to the over-production of four repeat tau, which somehow initiates the pathogenic process.
SUMMARY, SYNTHESIS AND SPECULATION
The clinical and pathological presentations of parkinsonism, both synucleinopathies and tauopathies, overlap and argue that the underlying defects may perturb relatively few common pathways for which there are a limited number of pathological responses (60). One rationale to understand these disorders is to identify the underlying genetic influences that result in different synuclein pathologies, in PD, LBD and MSA. Identifying the proteins, their interactions and the pathways affected will direct future epidemiological studies into environmental risk factors and the exploration of gene-environment interactions. Our task is to: (i) delineate which genetic methods will be most powerful to identify the underlying molecular components; (ii) identify the normal function of the defective proteins implicated in disease; and (iii) understand how those proteins and pathways are regulated and integrated. Despite the apparently low heritability suggested by cross-sectional twin studies (12), linkage analysis, with the caveats of reduced penetrance, variable expressivity and phenocopy, is proving a successful method with which to identify loci, genes and mutations leading to parkinsonism (8-10,20,22-24,34-35,49-53,57-59). The proteins identified may also be central to idiopathic PD (1). Limited family studies now suggest that the etiology of parkinsonism is multifactorial in which several susceptibility genes/mutations are involved. Given this conclusion, it is not surprising (with the exception of PSP; 57-59) that the majority of case-control studies for candidate gene associations have not proved reproducible. The problem lies not just with ascertainment or issues of misdiagnosis/under-diagnosis or in looking at the right candidate gene, but rather it is the underlying, naive assumption that disease in a sample is likely to originate from the same, common, founder mutation. This may be true in isolated populations, such as Finland or Iceland, where linkage disequilibrium mapping has proven powerful in diseases with simple, single gene etiologies, but is unlikely to hold true for idiopathic PD and the majority of studies. From the limited components identified to date, it is possible to speculate that these proteins may functionally overlap in a common pathway of cytoskeletal maintenance and intracellular vesicle transport (20,22,28,29,51-53,58). Identification of the susceptibility genes at ch2p, ch4p and other loci may lend support to this hypothesis (34,35). Hence, after >180 years, molecular genetic analysis of familial parkinsonism will finally allow us to refine the nosology that James Parkinson so carefully documented (61).
ACKNOWLEDGEMENTS
We thank Dennis Dickson for the figures. The work was supported by an NIH/NIA Program Project Grant (M.H., J.H. and K.G.H.), an NIH/NINDS Project grant (M.H.), the National Parkinson's Foundation (M.F.) and the Mayo Foundation.
REFERENCES
+To whom correspondence should be addressed. Tel: +1 904 953 7356; Fax: +1 904 953 7370; Email: hardy.john{at}mayo.edu
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