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

Sci Rep. 2017 Aug 8;7(1):7495. doi: 10.1038/s41598-017-07181-0.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dynamins / antagonists & inhibitors
  • Dynamins / genetics
  • Dynamins / metabolism
  • Gene Expression
  • Injections, Intraperitoneal
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Dynamics / drug effects*
  • Motor Activity / drug effects
  • Mutation
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / metabolism
  • Parkinson Disease, Secondary / pathology
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Pars Compacta / pathology
  • Protein Aggregates / drug effects
  • Quinazolinones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Striatonigral Degeneration / drug therapy*
  • Striatonigral Degeneration / genetics
  • Striatonigral Degeneration / metabolism
  • Striatonigral Degeneration / pathology
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Neuroprotective Agents
  • Protein Aggregates
  • Quinazolinones
  • alpha-Synuclein
  • Dnm1l protein, rat
  • Dynamins