Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein

The presynaptic alpha -synuclein is a prime suspect for contributing to Lew y pathology and clinical aspects of diseases, including Parkinson's disease , dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease . Here we examined the pathogenic mechanism of neuronal cell death induced by alpha -synuclein. The exogenous addition of alpha -synuclein caused a ma rked decrease of cell viability in primary and immortalized neuronal cells. The neuronal cell death appeared to be correlated with the Rab5A-specific endocytosis of alpha -synuclein that subsequently caused the formation of L ewy body-like intracytoplasmic inclusions. This was further supported by th e fact that the expression of GTPase-deficient Rab5A resulted in a signific ant decrease of its cytotoxicity as a result of incomplete endocytosis of a lpha -synuclein.