A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain.
The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS 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 βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies.
Division of Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan.
Masayo
M
Fujita
Shuei
S
Sugama
Kazunari
K
Sekiyama
Akio
A
Sekigawa
Tohru
T
Tsukui
Masaaki
M
Nakai
Masaaki
M
Waragai
Takato
T
Takenouchi
Yoshiki
Y
Takamatsu
Jianshe
J
Wei
Edward
E
Rockenstein
Albert R
AR
Laspada
Eliezer
E
Masliah
Satoshi
S
Inoue
Makoto
M
Hashimoto