Synphilin-1 inhibits alpha-synuclein degradation by the proteasome

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• 作者：Beatriz Alvarez-Castelao (1)
  José G. Casta?o (1) joseg.castano@uam.es
• 关键词：Synphilin – Synuclein – Proteasome – Proteolysis – Degradation – Parkinson – Synucleinopathies
• 刊名：Cellular and Molecular Life Sciences (CMLS)
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：68
• 期：15
• 页码：2643-2654
• 全文大小：595.1 KB
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• 作者单位：1. Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols- Universidad Autónoma de Madrid y Consejo Superior de Investigaciones Científicas (UAM-CSIC), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Idipaz, Facultad de Medicina UAM, 28029 Madrid, Spain
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Biomedicine
  Life Sciences
  Biochemistry
  
• 出版者：Birkh盲user Basel
• ISSN：1420-9071

文摘

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.