Parkin attenuates manganese‐induced dopaminergic cell death

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Abstract
Manganese as environmental factor is considered to cause parkinsonism and induce endoplasmic reticulum stress‐mediated dopaminergic cell death. We examined the effects of manganese on parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin in manganese‐induced neuronal cell death. Manganese dose‐dependently induced cell death of dopaminergic SH‐SY5Y and CATH.a cells and cholinergic Neuro‐2a cells, and that the former two cell types were more sensitive to manganese toxicity than Neuro‐2a cells. Moreover, manganese increased the expression of endoplasmic reticulum stress‐associated genes, including parkin, in SH‐SY5Y cells and CATH.a cells, but not in Neuro‐2a cells. Treatment with manganese resulted in accumulation of parkin protein in SH‐SY5Y cells and its redistribution to the perinuclear region, especially aggregated Golgi complex, while in Neuro‐2a cells neither expression nor redistribution of parkin was noted. Manganese showed no changes in proteasome activities in either cell. Transient transfection of parkin gene inhibited manganese‐ or manganese plus dopamine‐induced cell death of SH‐SY5Y cells, but not of Neuro‐2a cells. Our results suggest that the attenuating effects of parkin against manganese‐ or manganese plus dopamine‐induced cell death are dopaminergic cell‐specific compensatory reactions associated with its accumulation and redistribution to perinuclear regions but not with proteasome system.