Disorders with Synuclein
Pathology and
Parkinsonism
Laura L Kilarski, School of Medicine, Cardiff University, Cardiff, UK
Vladimir L Buchman, School of Biosciences, Cardiff University, Cardiff, UK
Huw R Morris, School of Medicine, Cardiff University, Cardiff, UK
Avarietyof neurodegenerativedisorders are classified as synucleinopathiesbasedon the
presence of prominent a-synuclein pathology. These diseases include Parkinson disease
(PD) and dementia with Lewy bodies (with neuronal Lewy body formation) and
multiple system atrophy (with glial cytoplasmic inclusions). The normal function of
a-synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PDcanbe
due to codingmutations ormultiplications of the a-synuclein gene (SNCA). The coding
mutations are thought to lead to a gain of function, in particular acceleration of the
formation of proto-fibrils. Duplications and triplications of SNCA lead to autosomal
dominant PDwith a gene dosage effect on age of onset and clinical severity; variants in
the SNCA promoter which lead to an upregulation of SNCA expression are associated
with an increased risk of sporadic PD.
Introduction
Synucleinopathies, a term encompassing a number of
diverse neurodegenerative diseases, are defined by the
accumulation of insoluble protein aggregates composed
of fibrillar a-synuclein (Spillantini et al., 1997). The most
prominent of these proteinaceous inclusions are spherical
eosinophillic Lewy bodies (LBs), which are found in
Parkinson disease (PD), Parkinson disease dementia
(PDD) and dementia with Lewy bodies (DLB), contain
a host of other components apart from a-synuclein, in-
cluding ubiquitin and a dense lipid core, and are found
predominantly in the neuronal cytoplasm. LBs have var-
iable morphology, and occur in diverse neural areas, in-
cluding brainstem, cortex, peripheral autonomic neurons
and the myenteric plexus. Glial inclusions containing a-
synuclein characterize another neurodegenerative dis-
ease, multiple system atrophy (MSA). In addition, a-
synuclein may accumulate in dystrophic neurites termed
Lewy neurites in PD, and axonal spheroids in
neurodegeneration with brain iron accumulation type 1
(NBIA-1; formerly Hallervorden–Spatz disease). In ad-
dition to PD, MSA and NBIA-1, other diseases may
sometimes have a-synuclein pathology in addition to
their normal hallmark pathology including familial and
sporadic Alzheimer disease (AD), Down syndrome, mo-
tor neuron diseases and tauopathies such as the Parkin-
sonism dementia complex of Guam (Jellinger, 2003). In
these diseases the a-synuclein pathology is considered to
be secondary to the primary neurodegenerative process.
Progressive neurodegeneration in specific brain regions is
a characteristic of synucleinopathies. However, the cel-
lular mechanisms underlying regional cell death and the
relationship between the normal function of a-synuclein,
aggregation, neural toxicity, neuronal loss and brain at-
rophy remain incompletely understood. In this review we
summarize the molecular, clinical and pathological fea-
tures of the major a-synuclein disorders: PD, PDD,
DLB, MSA and NBIA-1.
Structure of a-Synuclein
a-Synuclein is a small 19 kD protein that is highly con-
served in vertebrates. The a-synuclein gene SNCA is lo-
cated on chromosome 4q21 (PARK1 locus) and consists of
six exons, five of which are transcribed (Spillantini et al.,
1995). SNCA is alternatively spliced, producing three a-
synuclein isoforms, of which the 140 amino acid version is
the most abundant. a-Synuclein can undergo extensive
Advanced article
Article Contents
. Introduction
. Structure of a-Synuclein
. Function of a-Synuclein
. Parkinson Disease
. PARK1PD
. SNCA Promoter
. Other Causes of PD
. Dementia with Lewy Bodies
. Multiple System Atrophy
. Neurodegeneration with Brain Iron Accumulation Type 1
. Conclusions
Online posting date: 15
th
March 2009
ELS subject area: Genetics and Disease
How to cite:
Kilarski, Laura L; Buchman, Vladimir L; and, Morris, Huw R (March 2009)
Disorders with Synuclein Pathology and Parkinsonism. In: Encyclopedia
of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0006031
ENCYCLOPEDIA OF LIFE SCIENCES# 2009, John Wiley & Sons, Ltd. www.els.net 1

posttranslational modification, including phosphorylation
(Beyer, 2006). The primary sequence of a-synuclein con-
sists of three regions: the N-terminus repeat region, the
mid-protein nonamyloid component (NAC) domain and
the acidic C-terminus. The N-terminus comprises seven
imperfectly repeated 11-residue sequences, and is impli-
cated in a-synuclein’s ability to bind to phospholipid mem-
branes (e.g. synaptic vesicles) (Beyer, 2006; Kahle et al.,
2002). a-Synuclein is natively unfolded in the cytosol, and
normally only adopts a secondary amphipathic a-helical
structure, similar to the lipid-binding domains of class A2
apolipoproteins, upon membrane binding (Lee and
Trojanowski, 2006; Spillantini et al., 1997). The NAC do-
main is hydrophobic and contributes to a-synuclein’s pro-
pensity to aggregate. The C-terminal domain is highly
flexible and always remains unstructured (Kahle et al.,
2002; Figure 1).
Function of a-Synuclein
a-Synuclein is expressed in most brain regions with var-
ying intensity. Clayton and George (1998) point out that
it is most commonly found in areas involved in learning
and experience-dependent synaptic plasticity. In rodents,
mRNA (messenger ribonucleic acid) and protein levels
are especially high in the hippocampus, cortical layers 2,
3 and 5, as well as the olfactory bulb, whereas moderate
expression has been observed in the basal ganglia, the
raphe´ nuclei and locus coeruleus (Clayton and George,
1998 and references therein). a-Synuclein predominantly
localizes to synaptic terminals and has been shown to
transiently associate with pre-synaptic vesicles, especially
the reserve/resting pool. In addition, a-synuclein has
been found to co-localize with the synaptic protein
synapsin I (Kahle et al., 2002; Cabin et al., 2002). Con-
sequently, a-synuclein has been implicated in regulation
of the vesicular reserve pool.
Studies investigating transgenic mice lacking a-synu-
clein have yielded conflicting results. Knock-out (KO)
mice develop normally and show no gross morphological
abnormalities but some studies show a reduction in the
number of reserve pool vesicles and minor changes in
synaptic transmission (Murphy et al., 2000; Cabin
et al., 2002), whereas failing to replicate the observation
by Abeliovich et al. (2000) of a decrease in striatal do-
pamine levels. However, a host of studies suggest
some role for a-synuclein in dopaminergic neurotrans-
mission possibly by: regulation of tyrosine hydroxylase,
interaction with phospholipase D2, recruitment to ves-
icles, vesicle release probability and reuptake (Moore
et al., 2005; Beyer, 2006; Senior et al., 2008; Sidhu et al.,
2004).
It has also been suggested that a-synuclein may act as a
molecular chaperone, owing to its structural homology to
14-3-3 proteins, which also regulate tyrosine hydroxylase
(Ostrerova et al., 1999). Additional evidence came from
Chandra and colleagues who showed that overexpression
of a-synuclein attenuates degeneration of presynaptic ter-
minals in mice lacking cysteine-string protein-a (CSP-a).
CSP-a is a molecular chaperone, which interacts with sol-
uble NSF attachment receptor proteins (SNAREs), that
are necessary for vesicle trafficking. Mice deficient in both
a-synuclein and CSP-a suffer from accelerated neurode-
generation and progressive motor disturbances (Chandra
et al., 2005). These experiments suggest that a-synuclein
and CSP-a may have complementary functions as protec-
tive chaperones. In addition to a putative interaction with
SNAREs, a-synuclein also interacts with the proteasome
(Kahle et al., 2002). However, despite the wealth of exper-
imental data, the main function(s) of a-synuclein remains
uncertain.
Parkinson Disease
PD is the most common synucleinopathy, affecting 1% of
the population over the age of 65, and more than 4% of the
population over 85 (Tan and Skipper, 2007). The main
features of PD are tremor, bradykinesia, postural instabil-
ity and abnormal gait, as well as cognitive decline and de-
pression in up to 50% of cases. PD is characterized by
progressive degeneration of the substantia nigra pars
1
A30P E46K A53T
Acidic region
140
KTKEGV repeats
Amphipathic region
Hydrophobic
NAC domain
Figure 1 Structure of a-synuclein showing the location of the Mendelian coding mutations. Kindly provided by Dr. Morris
Disorders with Synuclein Pathology and Parkinsonism
ENCYCLOPEDIA OF LIFE SCIENCES# 2009, John Wiley & Sons, Ltd. www.els.net2