A ?-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain.

ABSTRACT: The discovery of ?-synuclein (?S) mutations has made a major contribution to the understanding of the pathogenesis of ?-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to ?-synuclein (?S) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H ?S develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H ?S tg mice with ?S tg mice, but not with ?S knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H ?S is pathogenic and cooperates with pathogenic ?S to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H ?S in familial DLB. Given the neuritic pathology of ?S in sporadic ?-synucleinopathies, it appears that alteration of ?S can contribute to the pathogenesis of a broad range of ?-synucleinopathies.

SUBMITTER: Fujita M 

PROVIDER: S-EPMC3060620 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature