期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 68, 期 15, 页码 2643-2654出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-010-0592-3
关键词
Synphilin; Synuclein; Proteasome; Proteolysis; Degradation; Parkinson; Synucleinopathies
资金
- CIBERNED
- [SAF-2008-00766]
- [CM SAL-0202]
Intracellular deposits of aggregated alpha-synuclein are a hallmark of Parkinson's disease. Protein-protein interactions are critical in the regulation of cell proteostasis. Synphilin-1 interacts both in vitro and in vivo with alpha-synuclein promoting its aggregation. We report here that synphilin-1 specifically inhibits the degradation of alpha-synuclein wild-type and its missense mutants by the 20S proteasome due at least in part by the interaction of the ankyrin and coiled-coil domains of synphilin-1 (amino acids 331-555) with the N-terminal region (amino acids 1-60) of alpha-synuclein. Co-expression of synphilin-1 and alpha-synuclein wild-type in HeLa and N2A cells produces a specific increase in the half-life of alpha-synuclein, as degradation of unstable fluorescent reporters is not affected. Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1 to degradation. Synphilin-1 inhibition of the proteasomal pathway of degradation of alpha-synuclein may help to understand the pathophysiological changes occurring in PD and other synucleinopathies.
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