Synphilin-1 inhibits alpha-synuclein degradation by the proteasome |
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Authors: | Beatriz?Alvarez-Castelao Email author" target="_blank">José?G?Casta?oEmail author |
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Institution: | 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,Madrid,Spain |
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Abstract: | 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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