期刊
BRAIN
卷 133, 期 -, 页码 2032-2044出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awq132
关键词
SNARE proteins; Parkinson's disease; alpha-synuclein; dopamine; neurodegenerative diseases
资金
- EU
- Italian Ministero della Salute [2006]
- Ente Cassa di Risparmio di Firenze, Italy
- European Action
- Medical Research Council [MC_U105184291] Funding Source: researchfish
- Parkinson's UK [G-0701] Funding Source: researchfish
- MRC [MC_U105184291] Funding Source: UKRI
The pre-synaptic protein alpha-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Mutations in the alpha-synuclein gene cause familial forms of Parkinson's disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human alpha-synuclein(1-120) that develops alpha-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinson's disease. We now show that in the striatum of these mice, as in Parkinson's disease, synaptic accumulation of alpha-synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length alpha-synuclein(1-140) or truncated alpha-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of alpha-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson's disease.
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