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Am J Pathol. 2001 Dec;159(6):2215-25.

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

Author information

1
Laboratory for Alzheimer's and Parkinson's Disease Research, the Department of Biochemistry, Ludwig Maximilians University, Munich, Germany. pkahle@pbm.med.uni-muenchen.de

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.

PMID:
11733371
PMCID:
PMC1850592
DOI:
10.1016/s0002-9440(10)63072-6
[Indexed for MEDLINE]
Free PMC Article

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