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Short Communications |
-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes
From the Department of Neurology,*
Allegheny University
of the Health Sciences MCP Division, Philadelphia, Pennsylvania; the
Department of Neuropathology and Neuroscience,
University of Tokyo, Tokyo, Japan; the Department of Pathologic
Sciences,
Manchester University, Manchester,
United Kingdom; the Center for Neurodegenerative Disease
Research,§
Department of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania; the Family Studies
Unit,¶
National Institute of Neurological
Disorders and Stroke, Clinical Center, Bethesda, Maryland; the
Department of Neurology,||
University of Massachusetts
Medical Center, Worcester, Massachusetts; the Departments of Medicine
(Neurology) and Medical Biophysics,**
University
of Toronto, Toronto, Ontario, Canada; the Department of
Pathology,
Indiana University
Medical Center, Indianapolis, Indiana; the Department of
Pathology,
University of
Washington School of Medicine, Seattle, Washington; the Department of
Neurology,§§
VA Medical Center and
University of Washington School of Medicine, Seattle, Washington; and
the Department of Neuropathology,¶¶
Institute of Psychiatry, London, United Kingdom
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein gene cause
familial Parkinson's disease (PD), and -synuclein is a
major component of Lewy bodies (LBs) in sporadic PD, dementia
with LBs (DLB), and the LB variant of Alzheimer's disease
(AD). To determine whether -synuclein is a component of LBs in
familial AD (FAD) patients with known mutations in presenilin
(n = 65) or amyloid precursor protein
(n = 9) genes, studies were conducted
with antibodies to -, ß-, and 
-synuclein. LBs
were detected with - but not ß- or -synuclein antibodies in
22% of FAD brains, and -synuclein-positive LBs were most
numerous in amygdala where some LBs co-localized with tau-positive
neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples
contained -synuclein-positive LBs, these inclusions may be
more common in FAD brains than previously reported.
Furthermore, -synuclein antibodies decorated LB filaments by
immunoelectron microscopy, and Western blots revealed that the
solubility of -synuclein was reduced compared with control brains.
The presence of -synuclein-positive LBs was not associated with any
specific FAD mutation. These studies suggest that insoluble
-synuclein aggregates into filaments that form LBs in many FAD
patients, and we speculate that these inclusions may compromise
the function and/or viability of affected neurons in the FAD
brain.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interest in elucidating the mechanisms that lead to LB formation has
intensified after the discovery that missense mutations in the
-synuclein gene on chromosome 4q21-23 cause familial PD.5, 6
These data strongly implicate -synuclein in the sequence of
abnormal events that result in the formation of LBs, and this notion is
supported by other studies demonstrating that -synuclein is a major
building block of LBs in sporadic PD, dementia with LBs (DLB), and
LBVAD.7-10
As LBs purified from DLB brains contain
full-length, partially truncated and insoluble high molecular weight
aggregates of -synuclein,9
a reduction in the solubility
of -synuclein may play a role in this process.9
Thus,
neurodegenerative diseases characterized by the accumulation of LBs may
result from alterations in wild-type -synuclein as well as from
mutant forms of this protein. Although two other proteins (ie, ß-
and -synuclein) are partially homologous with -synuclein, they
have not been detected in LBs,9
and it is uncertain whether
they play a role in other neurodegenerative disorders.
Evidence that LBs may result from pathogenic mutations other than those
affecting the -synuclein gene has emerged from studies showing that
LBs are present in the brains of some patients with familial AD (FAD)
and some Down's syndrome patients.11-14
Studies of the
prevalence and composition of LBs in FAD are important for elucidating
how mutations in the genes that cause hereditary forms of AD lead to
the accumulation of -synuclein into filamentous inclusions that may
compromise the function and viability of affected neurons in FAD and
other neurodegenerative disorders. However, cortical LBs are difficult
to detect even when anti-ubiquitin antibodies are used to label these
inclusions by immunohistochemistry. As ubiquitin is present in a
variety of brain lesions, it is not a specific marker of LBs. For
example, it is not always possible to distinguish ubiquitin-positive
LBs and NFTs from one another. Thus, the demonstration that antibodies
to -synuclein distinguish LBs from NFTs and a number of other
morphologically similar lesions by
immunohistochemistry7-10
prompted us to investigate the
prevalence and composition of LBs in the brains of patients with FAD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue Samples from FAD Cases
Previously characterized tissue samples were available for the
studies described here, and they came from 58 FAD patients with
mutations in the presenilin (PS)-1 gene, 9 FAD patients with mutations
in the amyloid precursor protein (APP) gene, and 7 FAD patients with a
mutation in the PS-2 gene.15-21
The pathological diagnosis
of definite AD was confirmed in the postmortem brains of these FAD
cases using recently revised neuropathological criteria.22
Five PS-1 cases were biopsy specimens from patients with early
symptoms. Although nearly all of the FAD patients had advanced dementia
at death, one patient with an A246E PS-1 mutation had preclinical AD,
and when this patient died of a myocardial infarction at age 51, his
brain showed numerous Aß plaques, with little neurofibrillary
degeneration (Braak stage I).23
The brain samples that were
available for study here (see Table 1
)
came from the following regions: substantia nigra
(n = 15), locus ceruleus
(n = 12), amygdala (n =
19), periamygdaloid entorhinal cortex (n = 18),
parahippocampal gyrus (at the level of the lateral geniculate nucleus;
n = 18), cingulate gyrus (n =
25), middle frontal cortex (n = 66), and
cerebellum (n = 11). We also examined tissue
blocks from organs other than the brain (ie, lung, heart, thyroid,
liver, pancreas, kidney, and adrenal gland) from one FAD case with an
M146L PS-1 mutation. The apolipoprotein E (ApoE) genotype of 62 of
these FAD cases was determined using methods described in previous
studies.15-21
All except 16 cases had the ApoE-
3/3
genotype (four were ApoE-2/3, 11 were ApoE-3/4, and one had the
ApoE-4/4 genotype).
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For comparison with the data from the FAD cases, we examined brain tissue from 8 patients who met criteria for DLB24 and 12 patients who met criteria for definite AD.22, 23, 25 These AD patients were considered to have sporadic disease as none had a first-degree relative with dementia.
Tissue Samples from Normal Control Cases
We examined brain tissue from 25 individuals who were documented to be cognitively normal before death by review of their medical records. None of these individuals met criteria for probable or definite AD after postmortem examination of their brains, and none of these brains had significant neuropathological abnormalities. Two control cases were unaffected members of the family with the PS-2 mutation, and one was an unaffected member of the PS-1 A246E family.
Immunohistochemistry and Anti-Synuclein Antibodies
Formalin fixed, paraffin-embedded sections cut at 6 µm were
stained with a panel of previously described monoclonal antibodies
(MAbs) and polyclonal antibodies9
raised to purified LBs
and HPLC-purified full-length recombinant -, ß-, and
-synucleins.26, 27
Immunohistochemistry was performed
using the avidin-biotin complex technique with 3,3'-diaminobenzidine
(DAB) as the chromogen and a modified antigen retrieval protocol
followed by counterstaining with hematoxylin.9, 28, 29
The
anti-synuclein antibodies used here included MAb LB509, which is
specific for -synuclein, MAb Syn207, which recognizes only
ß-synuclein, and mouse polyclonal antiserum 20, which detects only
-synuclein. Sections of cingulate gyrus and substantia nigra from a
patient with DLB were used as positive control tissue. Adjacent
sections stained with nonimmune serum in place of the primary antibody
served as negative controls. To determine whether LBs co-localized with
NFTs in the same neurons, we also performed double-label
immunohistochemistry using antibodies to tau and -synuclein using
methods similar to those reported elsewhere.9
Immunoelectron Microscopy
Immunoelectron microscopy (immuno-EM) was performed using sections
of amygdala from PS-1 cases known to have numerous LBs. Tissue samples
were fixed for 2 weeks in 10% formalin, embedded in paraffin, and
sectioned at 6 µm, and deparaffinized sections were probed with
-synuclein antibodies to identify LBs using a two-step
immunoperoxidase method with the chromogen DAB as
described.9
Small regions with immunostained LBs were
excised and processed for electron microscopic examination as reported
earlier.9
Western Blot Analysis
To examine the biochemical properties of -synuclein in LB-rich
regions of the FAD brain, we performed Western blot analysis on
extracts of the amygdala from three PS-1 cases (two with LBs in the
amygdala) and three age-matched normal controls. The methods for
extracting high-salt-soluble and Triton X-100-soluble -synuclein
from postmortem human brain tissue and for Western blot analysis were
identical to those reported recently by Baba et al.9
For
formic acid extracts, pellets were resuspended in 100 µl of 70%
formic acid and disrupted with three 1-second sonication bursts. Formic
acid was evaporated in an Automatic Environmental SpeedVac System
(Savant Instruments, Holbrook, NY). The dried pellets were
resuspended in 100 µl of SDS sample buffer and heated to 100°C for
10 minutes. These extracts were centrifuged at 40,000 rpm for 30
minutes in a TL-100 rotor before being used for Western blot analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein-positive LBs in the amygdala of 12 of
the 19 available samples (Figure 1, A and B)
. Some of these LBs appeared to
co-localize with NFTs in the same neurons, and this was confirmed by
double-label immunohistochemistry using antibodies to tau and
-synuclein (Figure 1, E and F)
. Although these
-synuclein-positive LBs most commonly appeared to be solid
inclusions, occasional LBs demonstrated an immunoreactive halo with a
clear core. Consistent with previous studies,7-10
-synuclein-immunoreactive LBs also were seen in cases of sporadic AD
with LBs (ie, LBVAD cases) and DLB, but not in normal control cases
(data not shown). Light cytoplasmic -synuclein immunoreactivity was
present in neurons of the amygdala in only 2 of 12 cases with sporadic
AD.
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-synuclein-positive LBs also were identified in
the adjacent periamygdaloid cortex (in 8 of 18 FAD samples examined),
the parahippocampal gyrus (in 4 of 18 FAD samples examined), the
cingulate gyrus (in 6 of 25 FAD samples examined), and areas 8 and 9 of
the frontal lobe (in 9 of 66 FAD samples examined). Fewer LBs were
stained by the -synuclein antibodies in the substantia nigra (2 of
15 FAD samples examined; Figure 1D
) and in the locus ceruleus (1 of 12
FAD samples examined). No -synuclein aggregates were seen in the
cerebellum of any of the FAD cases, and, aside from brain, there were
no -synuclein-stained abnormalities in any of the other organs from
the one FAD case studied here. Overall, 22% of the FAD cases contained
LBs in at least one brain sample.
In the FAD cases, -synuclein-positive dystrophic processes
(so-called Lewy neurites, Figure 1c
) were seen occasionally in areas
with LBs, including the amygdala, periamygdaloid cortex, cingulate
gyrus, and substantia nigra. They also were observed occasionally in
the CA2-3 region of the hippocampus, but these neurites were less
prominent than those described in DLB and LBVAD7-10
as
well as those seen here in control DLB brains. Significantly, no LBs,
dystrophic neurites, or other lesions were detected by antibodies to
either ß- or -synuclein in any of the FAD or control cases studied
here. Finally, the ApoE genotype did not exert an obvious influence on
the presence or distribution of -synuclein-positive LBs or Lewy
neurites in these FAD cases. For example, in the four FAD cases with
the most abundant -synuclein-stained LBs, three had an ApoE-3/3
genotype, and the other case had an ApoE-3/4 genotype.
The immuno-EM studies were performed to determine the ultrastructural
localization of -synuclein immunoreactivity in the LBs of the FAD
brain, and these experiments showed that -synuclein immunoreactivity
was localized primarily to the filaments in LBs, although some
-synuclein staining also was associated with the amorphous and
granular material interspersed between these filaments (Figure 1G)
.
Thus, as suggested by previous studies,9
these findings
imply that -synuclein is a major component of LB filaments.
Although limited amounts of unfixed, frozen FAD amygdala suitable for
biochemical studies were available, the Western blot analyses performed
on -synuclein-enriched extracts of the amygdala from three FAD and
two normal control brains revealed approximately equal amounts of
-synuclein in the high-salt-soluble fraction (Figure 2A)
. In formic-acid-extractable extracts,
high molecular mass -synuclein aggregates were detected in Western
blots of the two FAD amygdala samples (FAD1 and FAD2, Figure 2C
) where
-synuclein-containing LBs were present. The FAD case without LBs
(FAD3) and control brains lacked high molecular weight -synuclein
aggregates (Figure 2C)
. The reduction in monomeric -synuclein in
formic-acid-soluble extracts from the three FAD cases may reflect a
reduction in membrane-bound -synuclein, as a reduction was also
observed in the high-salt-insoluble, Triton X-100-soluble fractions
(Figure 2B)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein is a
component of LBs in the FAD brain, and we show here that antibodies to
- but not ß- or -synuclein label LBs in at least 22% of a
large series (n = 74) of FAD brains. Remarkably,
of those FAD brains from which the amygdala was available for analysis,
>60% showed -synuclein-immunoreactive LBs. Thus, the prevalence of
LBs in the brains of FAD patients with a known mutation in the PS-1,
PS-2, or APP genes may be far higher than that suggested by previous
studies. Furthermore, the antibodies to -synuclein-stained LBs in
many of the brain regions in which they have been shown to exist in DLB
and LBVAD, including the deeper layers of the parahippocampal gyrus and
cingulate cortex. However, classical appearing -synuclein-positive
nigral LBs and Lewy neurites (including those typically seen in CA2-3)
were less common in these FAD brains compared with the brains of
sporadic DLB and LBVAD patients.7-10
Although there are
few electron microscopic studies of LBs in FAD brains, our immuno-EM
data indicate that the filaments in these LBs are decorated by
antibodies to -synuclein and that these LBs closely resemble those
in PD, DLB, and LBVAD. In addition, just like the DLB brain, our
quantitative Western blot analyses demonstrated that -synuclein in
LB-rich regions of FAD brains aggregates into high molecular weight
species and is less soluble that -synuclein in normal brains.
Finally, -synuclein-stained lesions were not present in any tissues
outside of the brain in one of the FAD patients studied here, and the
antibodies to ß- or -synuclein did not stain LBs or other lesions
in the FAD brains.
The biological trigger for focal alterations in -synuclein
expression and/or solubility in FAD is unknown. However, our
observations are important because they extend the disorders in which
-synuclein aggregates into LBs to include degenerative diseases with
mutations unrelated to those causing familial PD. Thus, genetic
mutations involving genes other than the -synuclein gene may result
in a sequence of events that locally influence -synuclein and induce
LB formation.
The mechanism by which -synuclein forms into LBs is unknown.
However, alterations in the expression, metabolism, or biochemical
properties of -synuclein may lead to a reduction in solubility
followed by its incorporation into LB filaments. Our data showing an
increase in the pool of insoluble -synuclein in the FAD amygdala are
consistent with data from other studies showing a diminution in the
solubility of -synuclein recovered from neurodegenerative disease
brains with abundant LBs relative to normal brains.9
Whether or not epigenetic factors play a role in LB formation in the
brains of FAD patients is not clear at this time, but if our data on
the prevalence of -synuclein-positive LBs in the limited number of
amygdala samples from FAD patients accurately reflects the prevalence
of LBs in the brains of FAD patients with mutations in PS-1, PS-2, or
APP genes, then it is reasonable to infer that these mutations indeed
play a role in the formation of LBs from abnormal filaments composed of
-synuclein.
Our data confirm the findings of others showing that
-synuclein is a sensitive and specific protein marker of
LBs,7-10
although antibodies to -synuclein detected LBs
in the brains of all but two FAD patients in whom LBs had been
identified earlier using anti-ubiquitin antibodies and histochemical
stains.30
The reason LBs were not labeled by the antibodies
to -synuclein in these two FAD brains is not clear, but it is
possible that this reflects the low abundance of LBs in these brains or
that the inclusions identified previously were ubiquitin-positive
globose NFTs, which can be difficult to distinguish from
ubiquitin-positive LBs. Indeed, the latter problem undoubtedly accounts
for the fact that LBs are not recognized as common neuropathological
lesions in the brains of FAD patients due to mutations in PS-1, PS-2,
or APP genes, although LBs have been described by a number of authors
in AD cases that result from genetic abnormalities, including Down's
syndrome.11-14
Thus, our data suggest that pathogenic
mutations other than those that cause familial PD by affecting the
-synuclein gene may induce LB formation. Although there is no direct
evidence linking mutations in PS-1, PS-2, or APP genes to perturbations
in the metabolism of wild-type -synuclein, our data suggest that it
may be timely now to investigate potential interactions of the mutant
gene products that result from these well known FAD mutations similar
to several previous studies of other relevant protein
interactions.31, 32
For example, although co-localization
of NFTs and LBs has been described previously in the brains of patients
with sporadic DLB and PD,33
the present studies suggest
that genetic factors may play a role in the co-occurrence of these two
different inclusions in the same neuron. Thus, studies of the sequence
of events that underlie the formation of LBs, NFTs, and Aß plaques
may clarify the role of genetic and epigenetic factors in the
pathogenesis of these lesions.
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Acknowledgements |
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Footnotes |
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Supported by the National Institute on Aging of the National Institutes of Health (AG13623, AG09215, AG10124, AG05136, AG10133, and AG06781) and the Robert Potamkin Fund.
Accepted for publication July 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 1998, 152:879-884[Abstract]
-synuclein immunoreactivity. J Neuropathol Exp Neurol 1998, 57:334-337[Medline]
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L. E. Nee, M. C. Tierney, and C. F. Lippa Genetic aspects of Alzheimer's disease, Pick's disease, and other dementias American Journal of Alzheimer's Disease and Other Dementias, July 1, 2004; 19(4): 219 - 225. [Abstract] [PDF]
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G. Levy, E. D. Louis, H. Mejia-Santana, L. Cote, H. Andrews, J. Harris, C. Waters, B. Ford, S. Frucht, S. Fahn, et al. Lack of Familial Aggregation of Parkinson Disease and Alzheimer Disease Arch Neurol, July 1, 2004; 61(7): 1033 - 1039. [Abstract] [Full Text] [PDF]
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 C. A. Wilson, D. D. Murphy, B. I. Giasson, B. Zhang, J. Q. Trojanowski, and V. M.-Y. Lee Degradative organelles containing mislocalized {alpha}- and {beta}-synuclein proliferate in presenilin-1 null neurons J. Cell Biol., May 10, 2004; 165(3): 335 - 346. [Abstract] [Full Text] [PDF]
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 A. R. Saha, J. Hill, M. A. Utton, A. A. Asuni, S. Ackerley, A. J. Grierson, C. C. Miller, A. M. Davies, V. L. Buchman, B. H. Anderton, et al. Parkinson's disease {alpha}-synuclein mutations exhibit defective axonal transport in cultured neurons J. Cell Sci., March 1, 2004; 117(7): 1017 - 1024. [Abstract] [Full Text] [PDF]
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A. C. Pawlyk, B. I. Giasson, D. M. Sampathu, F. A. Perez, K. L. Lim, V. L. Dawson, T. M. Dawson, R. D. Palmiter, J. Q. Trojanowski, and V. M.-Y. Lee Novel Monoclonal Antibodies Demonstrate Biochemical Variation of Brain Parkin with Age J. Biol. Chem., November 28, 2003; 278(48): 48120 - 48128. [Abstract] [Full Text] [PDF]
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M. Necula, C. N. Chirita, and J. Kuret Rapid Anionic Micelle-mediated {alpha}-Synuclein Fibrillization in Vitro J. Biol. Chem., November 21, 2003; 278(47): 46674 - 46680. [Abstract] [Full Text] [PDF]
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E. Rogaeva, C. Bergeron, C. Sato, I. Moliaka, T. Kawarai, A. Toulina, Y-Q. Song, T. Kolesnikova, A. Orlacchio, G. Bernardi, et al. PS1 Alzheimer's disease family with spastic paraplegia: The search for a gene modifier Neurology, October 14, 2003; 61(7): 1005 - 1007. [Abstract] [Full Text] [PDF]
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K. A. Josephs, J. L. Holton, M. N. Rossor, H. Braendgaard, T. Ozawa, N. C. Fox, R. C. Petersen, G. S. Pearl, M. Ganguly, P. Rosa, et al. Neurofilament inclusion body disease: a new proteinopathy? Brain, October 1, 2003; 126(10): 2291 - 2303. [Abstract] [Full Text] [PDF]
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T. Antony, W. Hoyer, D. Cherny, G. Heim, T. M. Jovin, and V. Subramaniam Cellular Polyamines Promote the Aggregation of alpha -Synuclein J. Biol. Chem., January 24, 2003; 278(5): 3235 - 3240. [Abstract] [Full Text] [PDF]
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M. Hasegawa, H. Fujiwara, T. Nonaka, K. Wakabayashi, H. Takahashi, V. M.-Y. Lee, J. Q. Trojanowski, D. Mann, and T. Iwatsubo Phosphorylated alpha -Synuclein Is Ubiquitinated in alpha -Synucleinopathy Lesions J. Biol. Chem., December 6, 2002; 277(50): 49071 - 49076. [Abstract] [Full Text] [PDF]
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A. J. Harding, E. Stimson, J. M. Henderson, and G. M. Halliday Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease Brain, November 1, 2002; 125(11): 2431 - 2445. [Abstract] [Full Text] [PDF]
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D. W. Tsuang, A. M. Dalan, C. J. Eugenio, P. Poorkaj, P. Limprasert, A. R. La Spada, E. J. Steinbart, T. D. Bird, and J. B. Leverenz Familial Dementia With Lewy Bodies: A Clinical and Neuropathological Study of 2 Families Arch Neurol, October 1, 2002; 59(10): 1622 - 1630. [Abstract] [Full Text] [PDF]
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H. Miake, H. Mizusawa, T. Iwatsubo, and M. Hasegawa Biochemical Characterization of the Core Structure of alpha -Synuclein Filaments J. Biol. Chem., May 17, 2002; 277(21): 19213 - 19219. [Abstract] [Full Text] [PDF]
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M. S. Forman, M. L. Schmidt, S. Kasturi, D. P. Perl, V. M.-Y. Lee, and J. Q. Trojanowski Tau and {alpha}-Synuclein Pathology in Amygdala of Parkinsonism-Dementia Complex Patients of Guam Am. J. Pathol., May 1, 2002; 160(5): 1725 - 1731. [Abstract] [Full Text] [PDF]
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A. J. Harding, G. A. Broe, and G. M. Halliday Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe Brain, February 1, 2002; 125(2): 391 - 403. [Abstract] [Full Text] [PDF]
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 K. Gwinn-Hardy and A. A. Singleton Familial Lewy Body Diseases J Geriatr Psychiatry Neurol, January 1, 2002; 15(4): 217 - 223. [Abstract] [PDF]
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Y. Tsuboi, J. E. Ahlskog, H. Apaydin, J. E. Parisi, and D. W. Dickson Lewy bodies are not increased in progressive supranuclear palsy compared with normal controls Neurology, November 13, 2001; 57(9): 1675 - 1678. [Abstract] [Full Text] [PDF]
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R. J. Perrin, W. S. Woods, D. F. Clayton, and J. M. George Exposure to Long Chain Polyunsaturated Fatty Acids Triggers Rapid Multimerization of Synucleins J. Biol. Chem., November 2, 2001; 276(45): 41958 - 41962. [Abstract] [Full Text] [PDF]
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C. F. Lippa, M. L. Schmidt, V. M.-Y. Lee, and J. Q. Trojanowski {alpha}-Synuclein in Familial Alzheimer Disease: Epitope Mapping Parallels Dementia With Lewy Bodies and Parkinson Disease Arch Neurol, November 1, 2001; 58(11): 1817 - 1820. [Abstract] [Full Text] [PDF]
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R. Sharon, M. S. Goldberg, I. Bar-Josef, R. A. Betensky, J. Shen, and D. J. Selkoe alpha -Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins PNAS, July 31, 2001; 98(16): 9110 - 9115. [Abstract] [Full Text] [PDF]
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J. C. Janssen, P. L. Lantos, N. C. Fox, R. J. Harvey, J. Beck, A. Dickinson, T. A. Campbell, J. Collinge, D. P. Hanger, L. Cipolotti, et al. Autopsy-Confirmed Familial Early-Onset Alzheimer Disease Caused by the L153V Presenilin 1 Mutation Arch Neurol, June 1, 2001; 58(6): 953 - 958. [Abstract] [Full Text] [PDF]
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 F. J. S. LEE, F. LIU, Z. B. PRISTUPA, and H. B. NIZNIK Direct binding and functional coupling of {alpha}-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis FASEB J, April 1, 2001; 15(6): 916 - 926. [Abstract] [Full Text] [PDF]
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J. E. Galvin, V. M.-Y. Lee, and J. Q. Trojanowski Synucleinopathies: Clinical and Pathological Implications Arch Neurol, February 1, 2001; 58(2): 186 - 190. [Abstract] [Full Text] [PDF]
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B. Mehring, J. C.Y. Lin, D. Wilson, and C. F. Lippa Frontotemporal dementia with ubiquitinated inclusions: A case study of the regional distribution of hippocampal pathology American Journal of Alzheimer's Disease and Other Dementias, September 1, 2000; 15(5): 277 - 283. [Abstract] [PDF]
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P. J. Kahle, M. Neumann, L. Ozmen, V. Muller, H. Jacobsen, A. Schindzielorz, M. Okochi, U. Leimer, H. van der Putten, A. Probst, et al. Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant alpha -Synuclein in Human and Transgenic Mouse Brain J. Neurosci., September 1, 2000; 20(17): 6365 - 6373. [Abstract] [Full Text] [PDF]
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J. E. Galvin, B. Giasson, H. I. Hurtig, V. M.-Y. Lee, and J. Q. Trojanowski Neurodegeneration with Brain Iron Accumulation, Type 1 Is Characterized by {alpha}-, {beta}-, and {gamma}-Synuclein Neuropathology Am. J. Pathol., August 1, 2000; 157(2): 361 - 368. [Abstract] [Full Text] [PDF]
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J. C. Janssen, M. Hall, N. C. Fox, R. J. Harvey, J. Beck, A. Dickinson, T. Campbell, J. Collinge, P. L. Lantos, L. Cipolotti, et al. Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study Brain, May 1, 2000; 123(5): 894 - 907. [Abstract] [Full Text] [PDF]
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M. Okochi, J. Walter, A. Koyama, S. Nakajo, M. Baba, T. Iwatsubo, L. Meijer, P. J. Kahle, and C. Haass Constitutive Phosphorylation of the Parkinson's Disease Associated alpha -Synuclein J. Biol. Chem., January 7, 2000; 275(1): 390 - 397. [Abstract] [Full Text] [PDF]
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J. E. Galvin, K. Uryu, V. M.-Y. Lee, and J. Q. Trojanowski Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha -, beta -, and gamma -synuclein PNAS, November 9, 1999; 96(23): 13450 - 13455. [Abstract] [Full Text] [PDF]
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J. G. Culvenor, C. A. McLean, S. Cutt, B. C. V. Campbell, F. Maher, P. Jakala, T. Hartmann, K. Beyreuther, C. L. Masters, and Q.-X. Li Non-A{beta} Component of Alzheimer's Disease Amyloid (NAC) Revisited : NAC and {alpha}-Synuclein Are Not Associated with A{beta} Amyloid Am. J. Pathol., October 1, 1999; 155(4): 1173 - 1181. [Abstract] [Full Text] [PDF]
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P. H. Jensen, H. Hager, M. S. Nielsen, P. Hojrup, J. Gliemann, and R. Jakes alpha -Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356 J. Biol. Chem., September 3, 1999; 274(36): 25481 - 25489. [Abstract] [Full Text] [PDF]
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 M. Farrer, K. Gwinn-Hardy, M. Hutton, and J. Hardy The genetics of disorders withsynuclein pathology and parkinsonism Hum. Mol. Genet., September 1, 1999; 8(10): 1901 - 1905. [Abstract] [Full Text] [PDF]
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J. M. Souza, B. I. Giasson, Q. Chen, V. M.-Y. Lee, and H. Ischiropoulos Dityrosine Cross-linking Promotes Formation of Stable alpha -Synuclein Polymers. IMPLICATION OF NITRATIVE AND OXIDATIVE STRESS IN THE PATHOGENESIS OF NEURODEGENERATIVE SYNUCLEINOPATHIES J. Biol. Chem., June 9, 2000; 275(24): 18344 - 18349. [Abstract] [Full Text] [PDF]
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R. J. Perrin, W. S. Woods, D. F. Clayton, and J. M. George Interaction of Human alpha -Synuclein and Parkinson's Disease Variants with Phospholipids. STRUCTURAL ANALYSIS USING SITE-DIRECTED MUTAGENESIS J. Biol. Chem., October 27, 2000; 275(44): 34393 - 34398. [Abstract] [Full Text] [PDF]
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