α-Synuclein is an abundant presynaptic protein and a primary component of Lewy bodies in Parkinson disease. Although its pathogenic role remains unclear, in healthy nerve terminals α-synuclein undergoes a cycle of membrane binding and dissociation. An α-synuclein binding assay was used to screen for vesicle proteins involved in α-synuclein membrane interactions and showed that antibodies directed to the Ras-related GTPase Rab3a and its chaperone RabGDI abrogated α-synuclein membrane binding. Biochemical analyses, including density gradient sedimentation and co-immunoprecipitation, suggested that α-synuclein interacts with membrane-associated GTP-bound Rab3a but not to cytosolic GDP-Rab3a. Accumulation of membrane-bound α-synuclein was induced by the expression of a GTPase-deficient Rab3a mutant, by a dominant-negative GDP dissociation inhibitor mutant unable to recycle Rab3a off membranes, and by Hsp90 inhibitors, radicicol and geldanamycin, which are known to inhibit Rab3a dissociation from membranes. Thus, all treatments that inhibited Rab3a recycling also increased α-synuclein sequestration on intracellular membranes. Our results suggest that membrane-bound GTP-Rab3a stabilizes α-synuclein on synaptic vesicles and that the GDP dissociation inhibitor·Hsp90 complex that controls Rab3a membrane dissociation also regulates α-synuclein dissociation during synaptic activity.
α - Synuclein is an abundant presynaptic protein and a primary component of Lewy bodies in Parkinson disease . Although its pathogenic role remains unclear , in healthy nerve terminals α - synuclein undergoes a cycle of membrane binding and dissociation . An α - synuclein binding assay was used to screen for vesicle proteins involved in α - synuclein membrane interactions and showed that antibodies directed to the Ras - related GTPase Rab3a and its chaperone RabGDI abrogated α - synuclein membrane binding . Biochemical analyses , including density gradient sedimentation and co - immunoprecipitation , suggested that α - synuclein interacts with membrane - associated GTP - bound Rab3a but not to cytosolic GDP - Rab3a . Accumulation of membrane - bound α - synuclein was induced by the expression of a GTPase - deficient Rab3a mutant , by a dominant - negative GDP dissociation inhibitor mutant unable to recycle Rab3a off membranes , and by Hsp90 inhibitors , radicicol and geldanamycin , which are known to inhibit Rab3a dissociation from membranes . Thus , all treatments that inhibited Rab3a recycling also increased α - synuclein sequestration on intracellular membranes . Our results suggest that membrane - bound GTP - Rab3a stabilizes α - synuclein on synaptic vesicles and that the GDP dissociation inhibitor·Hsp90 complex that controls Rab3a membrane dissociation also regulates α - synuclein dissociation during synaptic activity .
Which is the primary protein component of Lewy bodies?
Which is the primary protein component of Lewy bodies ?
α-synuclein
alpha-synuclein α-synuclein αSyn