© 1999 Oxford University Press Human Molecular Genetics, 1999, Vol. 8, No. 10 Review 1901–1905
The genetics of disorders with synuclein pathology and
parkinsonism
Matt Farrer, Katrina Gwinn-Hardy, Mike Hutton and John Hardy+
Neurogenetics Laboratories, Departments of Pharmacology and Neurology, Birdsall Building, Mayo Clinic
Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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 α-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 α-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
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
α-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 andMSA 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.
Genetics of the diseases in which α-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 theisland of Panay (10). These latter are not reviewed herein. classic route to the identification of pathogenic loci.
+To whom correspondence should be addressed. Tel: +1 904 953 7356; Fax: +1 904 953 7370; Email: hardy.john@mayo.edu

1902 Human Molecular Genetics, 1999, Vol. 8, No. 10 Review
In 1996, Polymeropoulos and colleagues identified genetic
linkage to Lewy body parkinsonism in the Contursi kindred
(15,20). The α-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 α-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 pathogenicmutation can
be thought of as a ‘revertant’ (although there are other differences
between the human and mouse sequence; 25). Second, because a
fragment of α-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 α-
synuclein as a gene for Lewy body parkinsonism led immediately
to the realization that α-synuclein is a major component of Lewy
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 α-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 (α-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
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 α-synuclein; (c) ubiquitin (rhodamine, red) and α-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 α-synuclein antibodies in MSA.bodies (27).
The normal function of α-synuclein is unknown (28); however,
a role in synaptic transport of vesicles or in synaptic plasticity has
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.