Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis

EMBO Mol Med. 2018 Mar;10(3):e8166. doi: 10.15252/emmm.201708166.


Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient-derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.

Keywords: Protein–Protein interactions; amyotrophic lateral sclerosis; dynamin‐related protein 1; fission 1; mitochondrial dysfunction.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Behavior, Animal
  • Cell Differentiation / drug effects
  • Disease Models, Animal
  • Disease Progression*
  • Dynamins
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • GTP Phosphohydrolases / metabolism*
  • GTP Phosphohydrolases / pharmacology
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • Motor Activity / drug effects
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Muscular Atrophy / pathology
  • Mutation / genetics
  • Oxidative Stress / drug effects
  • Peptide Fragments / pharmacology
  • Protein Binding / drug effects
  • Stress, Physiological / drug effects
  • Superoxide Dismutase / metabolism


  • FIS1 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • P110 peptide
  • Peptide Fragments
  • Superoxide Dismutase
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dynamins