Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease
Sci Rep. 2017-08-08; 7(1):
DOI: 10.1038/s41598-017-07181-0
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1. Sci Rep. 2017 Aug 8;7(1):7495. doi: 10.1038/s41598-017-07181-0.
Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat
model of Parkinson’s disease.
Bido S(1)(2), Soria FN(1)(2), Fan RZ(3)(4), Bezard E(5)(6), Tieu K(7)(8).
Author information:
(1)University of Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(3)Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth,
United Kingdom.
(4)Florida International University, Miami, Florida, USA.
(5)University of Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, France. .
(6)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
.
(7)Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth,
United Kingdom. .
(8)Florida International University, Miami, Florida, USA. .
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.
DOI: 10.1038/s41598-017-07181-0
PMCID: PMC5548731
PMID: 28790323