Involvement of mortalin/GRP75/mthsp70 in the mitochondrial impairments induced by A53T mutant α-synuclein

Mutations and excessive accumulation of alpha-synuclein (alpha-syn) can lead to the degeneration of dopaminergic neurons, indicating a pivotal role of a-syn in the pathogenesis of Parkinson's disease (PD). Although how alpha-syn contributes to PD is still elusive, mitochondrial impairments have been reported to be implicated in. Mortalin, a molecular chaperone mainly located in mitochondria, has been linked to the pathogenesis of PD in recent studies. Moreover, some proteomics studies indicate that mortalin is associated with PD-related proteins, including alpha-syn. Therefore it is of interest to understand the function of mortalin in the mitochondrial disruption induced by A53T alpha-syn overexpression. The present study modulated the expression of mortalin and detected the effect of mortalin on the mitochondrial impairments induced by A53T alpha-syn in SH-SY5Y cells. Our data revealed that A53T alpha-syn could disrupt mitochondrial dynamics and increase the neuronal susceptibility to neurotoxin rotenone. The expression of mortalin decreased significantly in dopaminergic cells overexpressing A53T alpha-syn; furthermore, the down-regulation of mortalin could attenuate the disrupted mitochondrial dynamics by reducing alpha-syn translocation to mitochondria, suggesting that a compensatory mechanism of mortalin might be implicated in the pathogenesis of PD. (C) 2015 Elsevier B.V. All rights reserved.