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

The discovery of alpha-synuclein (alpha S) mutations has made a major contribution to the understanding of the pathogenesis of alpha-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to beta-synuclein (beta S) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H beta 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 beta S tg mice with alpha S tg mice, but not with alpha S knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H beta S is pathogenic and cooperates with pathogenic alpha S to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H beta S in familial DLB. Given the neuritic pathology of beta S in sporadic alpha-synucleinopathies, it appears that alteration of beta S can contribute to the pathogenesis of a broad range of alpha-synucleinopathies.