16
The
-Synucleinopathies: Parkinson’s Disease,
Dementia with Lewy Bodies, and Multiple
System Atrophy
MARIA GRAZIA SPILLANTINIa,c AND MICHEL GOEDERTb
aDepartment of Neurology and Brain Repair Centre, University of Cambridge,
Cambridge, UK
bMedical Research Council Laboratory of Molecular Biology, Cambridge, UK
ABSTRACT: Parkinson’s disease is the second most common neurodegenerative
disease, after Alzheimer’s disease. Neuropathologically, it is characterized by
the degeneration of populations of nerve cells that develop filamentous inclu-
sions in the form of Lewy bodies and Lewy neurites. Recent work has shown
that the filamentous inclusions of Parkinson’s disease are made of the protein

-synuclein and that rare, familial forms of Parkinson’s disease are caused by
missense mutations in the
-synuclein gene. Besides Parkinson’s disease, the
filamentous inclusions of two additional neurodegenerative diseases, namely,
dementia with Lewy bodies and multiple system atrophy, have also been found
to be made of
-synuclein. Recombinant
-synuclein has been shown to assem-
ble into filaments with similar morphologies to those found in the human dis-
eases and with a cross- fiber diffraction pattern. The new work has
established the
-synucleinopathies as a major class of neurodegenerative
disease.
Parkinson’s disease (PD) is the most common neurodegenerative movement dis-
order.1 Neuropathologically, it is defined by nerve cell loss in the substantia nigra
and the presence of Lewy bodies and Lewy neurites.2,3 In many cases, Lewy bodies
are also found in the dorsal motor nucleus of the vagus, the nucleus basalis of Mey-
nert, the locus coeruleus, the raphe nuclei, the midbrain Edinger-Westphal nucleus,
the cerebral cortex, the olfactory bulb, and some autonomic ganglia.4
Besides the substantia nigra, nerve cell loss is also found in the dorsal motor nu-
cleus of the vagus, the locus coeruleus, and the nucleus basalis of Meynert. Ultra-
structurally, Lewy bodies and Lewy neurites consist of abnormal filamentous
material.5 Lewy bodies and Lewy neurites also constitute the defining neuropatho-
logical characteristics of dementia with Lewy bodies (DLB), a common late-life de-
mentia that exists in a pure form or overlaps with the neuropathological
characteristics of Alzheimer’s disease (AD).6–9
cAddress for correspondence: M.G. Spillantini, Department of Neurology and Brain Repair
Centre, University of Cambridge, Cambridge, UK. Tel.: 44-1223-331145; fax: 44-1223-331174.
e-mail: mgs11@cam.ac.uk

17SPILLANTINI & GOEDERT: THE
-SYNUCLEINOPATHIES
Unlike PD, DLB is characterized by large numbers of Lewy bodies in cortical
brain areas, such as the entorhinal and cingulate cortices. However, Lewy bodies and
Lewy neurites are also present in substantia nigra in DLB, whereas hippocampal
Lewy neurites are found in a proportion of individuals with PD with a severe cogni-
tive impairment. Disorders with Lewy bodies and Lewy neurites thus present as a
clinical and neuropathological spectrum. Classical PD with minor cognitive impair-
ment and minimal cortical pathology is at one end of the spectrum, whereas severe
dementia, with or without antecedent parkinsonism, but with a severe Lewy body
and Lewy neurite pathology, is at the other end of the spectrum. Despite the fact that
the Lewy body was first described in 1912, its biochemical composition remained
unknown until the middle of 1997.
The discovery of a point mutation in the α-synuclein gene as a rare cause of fa-
milial PD has led us to the finding that α-synuclein is the major component of Lewy
bodies and Lewy neurites in idiopathic PD and DLB (FIG. 1).10–12 The Lewy body
pathology that is sometimes associated with other neurodegenerative diseases, such
as sporadic and familial Alzheimer’s disease, Down’s syndrome, and neurodegener-
ation with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), has also
been shown to be α-synuclein-positive.12–18 Moreover, the filamentous glial and
neuronal inclusions of multiple system atrophy (MSA) have been found to be made
of α-synuclein (FIG. 2).16,19–22 Taken together, this work has shown that PD, DLB,
and MSA are α-synucleinopathies.
FIGURE 1. Brain tissue from patients with dementia with Lewy bodies immunostained
for α-synuclein. (a,b) α-Synuclein-positive Lewy bodies and Lewy neurites in substantia ni-
gra stained with antibodies recognizing the amino-terminal (a) or the carboxy-terminal (b)
region of α-synuclein. Scale bar in b, 100 µm (for a and b). (c,d) α-Synuclein-positive Lewy
neurites in serial sections of hippocampus stained with antibodies recognizing the amino-
terminal (c) or the carboxy-terminal (d) region of α-synuclein. Scale bar in d, 80 µm (for c
and d). (e) α-Synuclein-positive intraneuritic Lewy body in a Lewy neurite in substantia ni-
gra stained with an antibody recognizing the carboxy-terminal region of α-synuclein. Scale
bar, 40 µm.