Journal Article

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Tieu, Kim, Fan, Rebecca Z., Bezard, Erwan, Soria, Federico N., Bido, Simone

2017

Overview

Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson’s disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo . To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 42/41 / 631/378/1689/1718 / 631/378/1934 / 64/60 / 82 / 82/1 / 82/51 / 82/80 / 96 / 96/63 / alpha-Synuclein - chemistry / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Animals / Corpus Striatum - drug effects / Corpus Striatum - metabolism / Corpus Striatum - pathology / Dynamin / Dynamins - antagonists & inhibitors / Dynamins - genetics / Dynamins - metabolism / Gene Expression / Humanities and Social Sciences / Injections, Intraperitoneal / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial Dynamics - drug effects / Motor Activity - drug effects / Movement disorders / multidisciplinary / Mutation / Neurodegeneration / Neurodegenerative diseases / Neuroprotection / Neuroprotective Agents - pharmacology / Oxidative stress / Oxidative Stress - drug effects / Parkinson Disease, Secondary - drug therapy / Parkinson Disease, Secondary - genetics / Parkinson Disease, Secondary - metabolism / Parkinson Disease, Secondary - pathology / Parkinson's disease / Pars Compacta - drug effects / Pars Compacta - metabolism / Pars Compacta - pathology / Protein Aggregates - drug effects / Quinazolinones - pharmacology / Rats / Rats, Sprague-Dawley / Rodents / Science / Science (multidisciplinary) / Striatonigral Degeneration - drug therapy / Striatonigral Degeneration - genetics / Striatonigral Degeneration - metabolism / Striatonigral Degeneration - pathology / Synuclein