title: Synphilin-1 inhibits alpha-synuclein degradation by the proteasome.
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.
authors.affiliation: 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.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Alvarez-Castelao
authors.forename: José G
authors.initials: JG
authors.lastname: Castaño
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000235:genetics; D051381:Rats; D013379:Substrate Specificity; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D061988:Proteasome Inhibitors; C118958:SNCAIP protein, human; D051844:alpha-Synuclein; D046988:Proteasome Endopeptidase Complex