Drp1 inhibition is protective against mitochondrial and autophagic impairment induced by alpha-synuclein

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with currently no effective neuroprotective or neurorestorative treatments available. Alpha-synuclein (α-syn) pathology is one of the key proteins involved in PD pathology, it has been found to induce mitochondrial dysfunction, yet the mechanism is not entirely understood. This thesis project tests the hypothesis that α-syn induces mitochondrial dysfunction through disruption of fission/fusion pathway. Using an inducible cell line, I successfully demonstrated that in a time-dependent manner α-syn overexpression induces mitochondrial fragmentation through disruption of fission/fusion dynamics, collapse of mitochondrial membrane potential, increased oxidative stress and impaired mitochondrial respiratory capacity. In addition, accumulation of protein aggregation was also observed due to impaired autophagy flux. More importantly, blocking the fission protein Dynamin Related protein 1 (Drp1) either genetically or pharmacologically confers protection against these abnormalities. Although further investigation is needed to better understand this protective mechanism, these results are consistent with our previous published data and those from other laboratories that Drp1 inhibition is a promising therapeutic target for PD.