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PMID: 11733371 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model.

The American journal of pathology ·Vol. 159 ·No. 6 ·2001-12-00 ·Pages 2215-25

Kahle PJ, Neumann M, Ozmen L, Müller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C

Abstract

alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.

MeSH Terms
Amino Acids/genetics Animals Binding Sites/genetics Blotting, Western Brain/metabolism,pathology Detergents Disease Models, Animal Humans Lewy Body Disease/genetics,metabolism,pathology Mice Mice, Inbred C57BL Mice, Transgenic Nerve Tissue Proteins/genetics,metabolism Solubility Subcellular Fractions Synaptosomes/metabolism Synucleins alpha-Synuclein
Chemicals
Amino Acids Detergents Nerve Tissue Proteins SNCA protein, human Snca protein, mouse Synucleins alpha-Synuclein
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Kahle P J
Laboratory for Alzheimer's and Parkinson's Disease Research, the Department of Biochemistry, Ludwig Maximilians University, Munich, Germany. [email protected]
Neumann M
Ozmen L
Müller V
Odoy S
Okamoto N
Jacobsen H
Iwatsubo T
Trojanowski J Q
Takahashi H
Wakabayashi K
Bogdanovic N
Riederer P
Kretzschmar H A
Haass C
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)63072-6
Email
[email protected]
Published
2001-12-00
Pages
2215-25
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850592
Subset
IM
External Links
PubMed source DOI: 10.1016/s0002-9440(10)63072-6 PMC Full Text View journal details
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