Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 159, Issue 6, Pages 2215-2225Publisher
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.1016/S0002-9440(10)63072-6
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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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