Alpha-synuclein binding to rab3a in multiple system atrophy

Glial cytoplasmic inclusions (GCIs) are characteristic protein deposits in multiple system atrophy (MSA), which are composed of abnormally phosphorylated, partially insoluble alpha-synuclein. In addition, recent studies have shown abnormal widespread accumulation of alpha-synuclein in neurons and neuronal processes, and in several regions including the thalamus and cerebral cortex in MSA. Combined alpha-synuclein and rab3a immunoprecipitation assays have shown alpha-synuclein/rab3a binding in the cerebellum and pons (in which GCIs were present) and in the cerebral cortex (area 8) (in which GCIs were absent) in MSA cases, but not in the cerebellum and cerebral cortex in age-matched controls. Similar findings were found in MSA-C and MSA-P cases (olivopontocerebellar atrophy and striatonigral degeneration types, respectively), thus indicating possible abnormal interactions of alpha-synuclein and rab3a in diseased brains. Abnormal alpha-synuclein binding to rab3a was also found in the substantia nigra but not in the cerebral cortex in Parkinson's disease. These findings suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA. Since rab3a is a member of the Ras super-family of small (21-25 kDa) GTP-binding proteins which is involved in the regulation of the internal trafficking, exocytosis and neurotransmission, and vesicle endocytosis, the present findings might suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA.