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Synucleinopathies
Clinical and Pathological Implications
James E. Galvin, MD, MSc;
Virginia M.-Y. Lee, PhD;
John Q. Trojanowski, MD, PhD
Arch Neurol. 2001;58:186-190.
ABSTRACT
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The synucleinopathies are a diverse group of neurodegenerative disorders
that share a common pathologic lesion composed of aggregates of insoluble  -synuclein
protein in selectively vulnerable populations of neurons and glia. Growing
evidence links the formation of abnormal filamentous aggregates to the onset
and progression of clinical symptoms and the degeneration of affected brain
regions in neurodegenerative disorders. These disorders may share an enigmatic
symmetry, ie, missense mutations in the gene encoding for the disease protein
(-synuclein) cause familial variants of Parkinson disease as well as
its hallmark brain lesions, but the same brain lesions also form from the
corresponding wild-type brain protein in the more common sporadic varieties
of Parkinson disease. It is likely that clarification of this enigmatic symmetry
in 1 form of synucleinopathy will have a profound impact on understanding
the mechanisms underlying all these disorders. Furthermore, these efforts
will likely lead to novel diagnostic and therapeutic strategies in regard
to the synucleinopathies.
INTRODUCTION
The synucleins are a family of soluble proteins whose function is not
well understood. These proteins are characterized by an acidic carboxyl terminus
and 5 or 6 imperfect repeat motifs (KTKEGV) distributed throughout the aminoterminus.1-6
There are currently 4 members of the synuclein family that range between 127
to 140 amino acids in length. The first synuclein was described in 1988, after
it was purified from the Torpedo electroplaque and from rat brain,7 and it is known as
-synuclein (S).1-6,8
Later, however, it was also named the nonamyloid component (NAC) of plaque precursor protein after the NAC peptide was isolated
from amyloid-rich senile plaques (SPs) of brains of patients with Alzheimer
disease (AD)1-6,8
and shown to be identical to residues 61 to 95 of S. The S gene
then was mapped to chromosome 4q21.3-q22.1-2,9
The second member of the synuclein family, which now is known as
 -synuclein (S), is highly homologous to S.
It was originally isolated from the bovine brain and initially termed phosphoneuroprotein-14.1-6,10
The gene for S was mapped to chromosome 5q35.1-2,6
Because of the similar localization of both proteins, predominantly in the
presynaptic terminals of neurons, it has been speculated that S and S
may be involved in synaptic function.1-2,6
The third member of the synuclein family, now designated
 -synuclein (S), was isolated from breast cancer tissue
and initially termed breast cancer gene–specific product
1.1-2,6, 11-12
In addition to breast tissue, S is expressed in the brain and spinal
cord but is most abundant in the peripheral nervous system. Unlike S
and S, S is predominantly cytosolic in location,1, 11-12
and it has been mapped to chromosome 10q23.1-2,11-12
The most recently described member of the synuclein family is termed synoretin, but the gene encoding this protein has not been
mapped at this time.13 Synoretin is also distributed
throughout the cytoplasm, but it is mainly expressed in the retina, and there
is only low-level expression in the brain.1, 13
While S has been extensively implicated in mechanisms underlying neurodegenerative
disorders,1-6,14-16
until recently, there has been no evidence to suggest a role for S and S
in neurologic disease.14
 S IN PARKINSON DISEASE AND DEMENTIA WITH LEWY BODIES
Parkinson disease (PD) is the most common neurodegenerative movement
disorder, and it is well characterized clinically as well as pathologically.1, 14-15,17 It
is estimated that there are more than 500 000 patients with PD in the
United States alone. The cardinal clinical features of PD include (1) bradykinesia,
(2) cogwheel rigidity, (3) resting tremor, and (4) postural instability. Dementia
is a variable manifestation of PD, but it occurs in approximately 40% of patients
during the protracted course of the disease. Pathologically, PD is characterized
by the loss of the dopaminergic neurons from the substantia nigra pars compacta
(SNpc), the presence of extracellular melanin released from degenerating neurons,
reactive gliosis, and eosinophilic intracytoplasmic inclusions known as Lewy
bodies (LBs) in residual SNpc neurons.1, 4, 15-18
The LB, first described by Frederick Lewy in 1913 in the basal forebrain,19 is present in essentially all cases of PD, and the
detection of LBs in SNpc neurons of the postmortem brain is required to establish
a definite diagnosis of PD.1, 4, 15-18
The primary neurochemical deficit in PD is the loss of dopaminergic projections
to the striatum as a result of the massive degeneration of dopaminergic nigral
neurons. This neurochemical defect can be partially corrected by the administration
of levodopa and related therapies that substitute for the loss of SNpc neurons,
which thereby ameliorates at least the motor impairments of PD, particularly
early in the course of the disease.1, 15, 17
However, in addition to the dopaminergic neurons of the SNpc, other populations
of neuromelanin-containing and non–neuromelanin-containing neurons in
the brainstem and basal forebrain degenerate and accumulate LBs that are similar
to those found in the SNpc, possibly accounting in part for many of the secondary
clinical features in PD, including autonomic instability, seborrhea, sleep
disturbances, and possibly dementia.1, 17
While nigral and other subcortical LBs were well documented in PD, it
was not until 1961 that Okazaki et al20 described
cortical LBs in a patient with severe dementia and quadriparesis.1, 17 This original description opened investigation
into a new category of late-life dementias, collectively referred to as dementia
with Lewy bodies (DLB).1, 3, 5, 14-18
This brain disorder may be the second most common form of dementia after AD.
Clinical features that are most characteristic of DLB include (1) progressive
dementia with a fluctuating clinical course, (2) extrapyramidal signs (typically
bradykinesia and cogwheel rigidity but rarely resting tremor), (3) prominent
visual hallucinations, and (4) increased sensitivity to neuroleptic medications.
In the decades that followed the original descriptions of the neuropathologic
and clinical features of PD, a large body of experimental evidence developed
that correlated the neuropathologic features of PD with its different clinical
manifestations. However, recent dramatic insight and clues into the cellular,
molecular, and genetic pathobiology of PD have now emerged that challenge
the conventional and traditional views about the basic mechanisms underlying
brain degeneration in PD as well as the common, although unclear, overlap
between PD and AD.1, 5, 14-18
Recent evidence highlights the clinical heterogeneity of both PD and AD.1-6,14-18
Patients with PD may develop an AD-like dementia in the latter stages of the
disease, and as many as 25% to 35% of patients with AD develop extrapyramidal
signs during their illness.1, 15, 17-18
Investigators have demonstrated by immunohistochemical examination that
LBs contain many different cytoskeletal and noncytoskeletal proteins, but
before 1997 the 2 most consistently described proteins were neurofilament
and ubiquitin.1, 17 However, in
1997, a landmark finding by Polymeropoulos and coworkers21
detailed 5 Mediterranean families with autosomal dominant PD caused by a missense
mutation in the S gene leading to an A-to-T substitution at amino acid
53. Subsequently, a second mutation was described in 1 family of German origin
with an A-to-P substitution at amino acid 30.22
Furthermore, in 1997 and shortly thereafter, it was discovered that antibodies
specific for S detect numerous LBs and dystrophic Lewy neurites (LNs)
in sporadic PD and DLB.1-6,14-16,18, 23
There is now mounting evidence to support the concept that S
is the primary building block of the fibrillary component of LBs.1-6,14-16
Antibodies that recognize S stain LBs more intensely and more consistently
than antibodies directed against other protein components, and immunoelectron
microscopic studies have demonstrated that LB fibrils are intensely decorated
with S antibodies in situ.1-6,14-16
There is ample evidence that insoluble S filaments accumulate in brains
of patients with PD and DLB and that recombinant S protein can assemble
in vitro into elongated filaments with ultrastructural features similar to
those of LB filaments visualized in situ.1, 24
In addition, S aggregation within the dystrophic LNs is associated
with brain regions rich in perikaryal LBs, particularly the CA2/3 region of
the hippocampus. Accordingly, it appears increasingly plausible that this
pathologic finding may play an important role in the loss of neuronal function.1, 5, 14, 16
Increasing interest in the pathobiological features of S has
been driven in part by the expanding spectrum of LB-related disorders (Figure 1).1-6,14-18
For example, S-rich cortical LBs similar to those found in the mesencephalic
neurons of patients with PD have also been detected in cortical neurons of
some demented patients.1-6,14-18
The presence of numerous cortical and subcortical LBs, SPs, and neurofibrillary
tangles defines a subtype of AD referred to as the LB variant
of AD.1, 5, 14-15,17-18
Furthermore, the presence of abundant cortical LBs in the brains of patients
with a late-life AD-like dementia who present with extrapyramidal and neuropsychiatric
symptoms without significant SPs or neurofibrillary tangles is diagnostic
of the disorder referred to as DLB.1-6,14-18
Notably, it appears that the number of cortical LBs correlates with the severity
of dementia and that the burden of S-immunoreactive LBs is the most
specific and sensitive marker for dementia in patients with PD and DLB.15, 17, 25 In addition, LBs
have been described in the amygdala of patients with familial forms of AD
with mutations in the genes for the amyloid precursor protein and presenilin-1
and -21-2,5, 26
as well as in the brains of aged patients with Down syndrome.1-2,5, 27
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Clinical spectrum of Lewy body (LB) disorders. Schematic representation
shows diverse neurodegenerative disorders that share a common pathologic lesion,
ie, LBs. The 2 prominent clinical features in neurodegenerative disorders
are extrapyramidal symptoms (typified by Parkinson disease [PD]) and a memory
disorder (typified by Alzheimer disease [AD]). These clinical symptoms overlap
substantially, with up to 40% of patients with PD developing cognitive decline
and up to 35% of patients with AD developing extrapyramidal symptoms. Along
this spectrum, there is a population of patients with a late-life dementia
with mild to moderate extrapyramidal symptoms and memory disturbances, referred
to as dementia with Lewy bodies (DLB). The predominant clinical features of
these patients are behavioral abnormalities and visual hallucinations. Their
brains are characterized pathologically by abundant neocortical and subcortical
LBs. See the text for a more complete description of clinical syndromes.
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In recognition that LB dementias may be the second most common form
of neurodegenerative dementing illness in the elderly after AD and because
of the confusion regarding nomenclature and diagnostic criteria for LB dementias,
a consortium on DLB formalized standard procedures for the definitive pathological
and clinical diagnosis of this disorder.1-6,14-18
The recommendations of the consortium included the use of antibodies against
ubiquitin to detect LBs. However, ubiquitin immunoreactivity is present in
a number of neurodegenerative lesions, some of which may be very difficult
to distinguish from LBs (eg, neurofibrillary tangles).1, 17
Thus, the use of antibodies specific for S to detect LBs and LNs is
a much more specific technique that should improve the standardization of
the postmortem diagnosis of neurodegenerative diseases characterized by LBs
and LNs as well as other diseases with S-immunoreactive lesions.1, 25
IMPLICATION OF S IN OTHER
NEURODEGENERATIVE DISEASES
Significantly, S has been implicated as a major component of
the tubulofilamentous inclusions found in oligodendrocytes in multiple system
atrophy known as glial cytoplasmic inclusions (GCIs).2-3,5-6,28
Multiple system atrophy consists of a syndrome complex with parkinsonism and
a combination of cerebellar, autonomic, and gait abnormalities as well as
variable cognitive decline. These disorders include Shy-Drager syndrome, striatonigral
degeneration, and olivopontocerebellar atrophy, all of which are characterized
by the presence of S-immunoreactive GCIs throughout the neocortex,
hippocampus, brainstem, spinal cord, and dorsal root ganglia. In addition,
neurodegeneration with brain iron accumulation, type I (also referred to as adult neuroaxonal dystrophy or Hallervorden-Spatz
syndrome), is a rare neurodegenerative disorder characterized clinically
by parkinsonism, cognitive decline, cerebellar signs, and bulbar symptoms.
Pathologically, iron deposition is found in the globus pallidus, red nucleus,
SNpc, and dentate nucleus of the cerebellum, and axonal swellings known as spheroids are seen. In addition, both GCIs and LB-like
neuronal cytoplasmic inclusions are seen in both cortical and subcortical
structures. The spheroids, GCIs, and neuronal cytoplasmic inclusions are all
easily detected by antibodies against S.28-29
The S component of brain regions with these lesions is largely found
in the insoluble fractions, similar to the pattern of distribution seen in
LB disorders. Furthermore, axonal lesions after traumatic brain injury also
have been demonstrated recently to express S.29
Besides the above-mentioned disorders, there are several other neurodegenerative
diseases in which S-immunoreactive lesions may contribute to the pathologic
features seen in the disorder but may not be the major protein constituent
of the lesion. For example, a subset of the Pick bodies within the dentate
gyrus of the hippocampus in patients with Pick disease is strongly immunoreactive
for S; however, the major building block of Pick bodies appears to
be tau protein.3, 5, 16
In addition, glial inclusions in amyotrophic lateral sclerosis also show S
immunoreactivity (J.E.G., V.M.-Y.L., J.Q.T., unpublished data, 1999).
A ROLE FOR  S AND  S IN NEUROLOGIC DISEASE
It has been demonstrated recently that S, S, and S
are expressed in olfactory epithelium, especially the olfactory receptor neurons.
These neurons retain the ability to regenerate continuously throughout life.30 Although olfactory dysfunction is a feature of several
neurodegenerative diseases and dystrophic neurites were detected with antibodies
to S and S in the postmortem examination of olfactory epithelium
of patients with synucleinopathies, similar patterns of pathologic and normal
synuclein expression were seen in control subjects and patients with other
neurodegenerative diseases. This suggests that synuclein may play a role in
the regeneration and plasticity of adult human olfactory epithelium.30
Although S and S are abundant in the brain, initially they
had not been implicated in a neurodegenerative disease.14
However, it was recently demonstrated that hilar neurons in the hippocampus
of patients with PD and DLB were surrounded by accumulations of S-
and S-immunoreactive vesicles in presynaptic terminals.14
This pathologic finding was not seen in normal control subjects or in patients
with other neurodegenerative disorders, such as AD or Pick disease. The marked
abundance and variable size of these profiles suggested that they reflect
pathologic aggregation of S and S in the axon terminals of dentate
gyrus mossy fiber projections to the hilar neurons. The abundance of these
vesicles appeared to parallel the presence of S-immunoreactive LNs
in the CA2/3 region of the hippocampus and LBs in the entorhinal cortex of
patients with PD and DLB. Moreover, axonal spheroidlike lesions were identified
in the molecular layer of the dentate gyrus of PD and DLB, with antibodies
against S but not with antibodies to S or S. The synuclein-rich
lesions colocalized with other presynaptic proteins (ie, synaptophysin, synapsin,
and synatobrevin), suggesting that the pathologically altered axon terminals
or their corresponding synapses may be dysfunctional. This finding is significant
because it describes brain abnormalities in a neurodegenerative disease that
contains pathologic accumulation of not only S but also S and S.
Accordingly, one can conclude that S and S, in addition to S,
may play mechanistic roles in the onset or progression of several neurodegenerative
disorders. Indeed, because S pathologic features may be seen in other
neurodegenerative diseases as well as in a few normal individuals, S
and S pathologic features may be more specific to LB disorders.14
POTENTIAL MECHANISMS OF NEURONAL DYSFUNCTION
The role S plays in amyloid plaque formation has been called
into question, as several investigators have failed to confirm the initial
observation of NAC immunoreactivity in AD SPs.1, 31
Monoclonal antibodies to the NAC peptide have been demonstrated to stain LBs
and LNs, but they failed to stain any AD SPs.31
It is possible that, in the original isolation of the NAC peptide, the brain
regions that were demonstrated to contain SPs also contained abundant S-rich
LNs, and the contaminating LNs may have served as the source for the S
in isolated amyloid plaques.
The finding of insoluble lesions in different neuronal and glial cell
populations involving highly varied clinical syndromes suggests that many
of these neurodegenerative disorders share a commonality.1-6,14-18,32
Despite the fact that these syndromes express different phenotypic symptoms
and pathologic lesions, the mechanisms underlying filament formation may be
similar. Notably, the assembly of normally soluble protein subunits into insoluble
filaments in these neurodegenerative diseases does not occur de novo in normal
brain.1, 24 Thus, one can conceptualize
that another way to approach these different disorders is to consider the
disease state as one of an abnormality in protein metabolism (ie, synucleinopathy)1-6,14-18,32
(Table 1). It is plausible that
the common feature of synucleinopathies is the mechanisms underlying the posttranslational
modification of synuclein that alters the biophysical properties of this synaptic
protein, leading to the formation of insoluble fibrillar aggregates. These
biochemical changes most likely lead to a cascade of cellular responses that
result in neuronal dysfunction and death that present as a recognizable clinical
and pathologic phenotype.1-6,14-18,32
It is reasonable to propose that future investigative efforts that pursue
molecular analyses of shared protein abnormalities across several disorders
(ie, synuclein protein in PD; DLB; familial AD; multiple system atrophy; neurodegeneration
with brain iron accumulation, type I, or tau protein in Pick disease; frontotemporal
dementia; prion disease; corticobasal degeneration; and progressive supranuclear
palsy) will provide insights into disease mechanisms underlying 1 or more
neurodegenerative disorders characterized by abundant filamentous lesions.
In this manner, preventive and potentially curative strategies for these disorders
may be possible.
No doubt, the development of transgenic animal models that recapitulate
the key pathologic aspects of human neurodegenerative disease will help answer
questions regarding the mechanisms leading to neurodegenerative disease. At
present, there has been only 1 published report suggesting that mice that
overexpress S develop perikaryal and nuclear S aggregates, although
these aggregates are not fibrillar and it is unclear whether these aggregates
are associated with neuronal dysfunction or loss.33
It is likely that many reports of other efforts to generate S-, as
well as S- and S-, transgenic mice will soon appear.
Further studies will be necessary to determine to what extent insoluble
aggregates of S as LBs, LNs, GCIs, or spheroids can lead to the demise
of neurons; however, current evidence suggests that their presence may have
several deleterious effects. First, the meshwork of S filaments may
serve as a molecular "trap" for proteins destined for transport within axons,
preventing transit of vital proteins from soma to axon terminals. As a result,
distal regions of axons and dendrites may be deprived of proteins essential
for survival or function, resulting in a loss of structural and molecular
integrity of the axons and dendrites. Second, the presence of vital cytoskeletal
proteins entrapped within the S filaments may deprive axons of important
structural integrity and cause a "dying back" process that may "disconnect"
the SNpc from the basal ganglia (in the case of PD) and one cortical region
from another (in DLB, for example).1, 5, 14, 17
Third, the presence of S aggregates in neurites and axons (ie, dystrophic
LNs) and S in perforant pathway projections also may contribute to
the dysfunction of the nervous system, possibly by impeding axonal transport.1, 14 Last, recent studies demonstrating
the accumulation of synuclein and other presynaptic proteins in the degenerating
terminals of the hippocampal perforant pathway projections could interfere
with the unidirectional flow of information in this vital circuit important
in memory and behavior.14 Thus, the accumulation
of a normally soluble protein into pathologic insoluble aggregates could not
only serve as a marker of disease but also compromise the function and viability
of neurons.1, 5, 14, 17
Efforts to further elucidate the pathobiological features of synuclein proteins
are likely to lead to improved strategies for antemortem diagnosis and the
development of novel therapeutic interventions for a diverse group of neurodegenerative
disorders, including PD; DLB; LB variant of AD; multiple system atrophy; neurodegeneration
with brain iron accumulation, type I; and other synucleinopathies.
AUTHOR INFORMATION
Accepted for publication May 10, 2000.
This work was supported by grants AG10124 and AG09215 from the National
Institute on Aging, Bethesda, Md, and a Pioneer award from the Alzheimer's
Association, Chicago, Ill.
We thank Benoit I. Giasson, PhD, and John E. Duda, MD, for their critical
review of the manuscript.
Corresponding author and reprints: James E. Galvin, MD, MSc, Alzheimer's
Disease Research Center, Department of Neurology, Campus Box 8111, Washington
University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110 (e-mail: galvinj{at}neuro.wustl.edu).
From the Alzheimer's Disease Research Center, Department of Neurology,
Washington University School of Medicine, St Louis, Mo (Dr Galvin); and Center
for Neurodegenerative Disease Research, Department of Pathology and Laboratory
Medicine, University of Pennsylvania, Philadelphia (Drs Galvin, Lee, and Trojanowski).
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