Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein.
The presynaptic alpha-synuclein is a prime suspect for contributing to Lewy 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 marked 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 Lewy body-like intracytoplasmic inclusions. This was further supported by the fact that the expression of GTPase-deficient Rab5A resulted in a significant decrease of its cytotoxicity as a result of incomplete endocytosis of alpha-synuclein.
Sung
J Y
JY
Department of Pharmacology and Brain Research Institute, the Department of Microbiology, and the Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
Kim
J
J
Paik
S R
SR
Park
J H
JH
Ahn
Y S
YS
Chung
K C
KC
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D003593:Cytoplasm / Q000648:ultrastructure; D004705:Endocytosis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D051843:Synucleins; D051844:alpha-Synuclein; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D020696:rab5 GTP-Binding Proteins