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-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
Missense mutations in the 
-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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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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P. H. ST GEORGE-HYSLOP Genetic Factors in the Genesis of Alzheimer's Disease Ann. N.Y. Acad. Sci., December 1, 2000; 924(1): 1 - 7. [Abstract] [Full Text] [PDF]
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M. G. SPILLANTINI and M. GOEDERT The {alpha}-Synucleinopathies: Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy Ann. N.Y. Acad. Sci., December 1, 2000; 920(1): 16 - 27. [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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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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