Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

Am J Pathol 159(6): 2215-25

Authors/Editors: Kahle PJ
Neumann M
Ozmen L
Muller V
Odoy S
Okamoto N
Jacobsen H
Iwatsubo T
Trojanowski JQ
Takahashi H
Wakabayashi K
Bogdanovic N
Riederer P
Kretzschmar HA
Haass C
Publication Date: 2001
Type of Publication: Journal Article
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.

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