Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein

MARTINEZ J; ALAIMO A; GOROJOD R; PORTE ALCON S; FUENTES F.; COLUCCIO LESKOW F.; KOTLER M

MOLECULAR AND CELLULAR NEUROSCIENCES.

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2018 vol. 88 p. 107 - 117

1044-7431

Parkinson´s disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons fromsubstantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component ofthe Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibitionof autophagy both events associated to the intracellular accumulation of α-synuclein. Themechanism by which these events contribute to neural degeneration remains unknown. In the present work weinvestigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells,an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causesmoderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrialfragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 preventedboth mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showedactivated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagyis triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 andDrp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findingspresented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Betterunderstanding of the molecular interaction between these processes could give rise to novel therapeutic methodsfor PD prevention and amelioration.