Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS), which clinically manifests by progressive muscle atrophy and paralysis, is a fatal neurodegenerative disease characterized by the death of upper and lower motor neurons (MN; Boillee et al, 2006)
We determined if this mitochondrial fragmentation was mediated by Drp1/fission 1 (Fis1) interaction, using P110, a heptapeptide conjugated to TAT47–57 (TAT, for intracellular delivery) that selectively inhibits the interaction between Drp1 and Fis1, one of its adaptor proteins on the mitochondria (Qi et al, 2013)
To confirm that Fis1 is critical for the mitochondrial structural changes observed in ALS patient-derived fibroblasts, we transiently knocked down the expression Fis1 (Fig EV1A) and observed a significant recovery in mitochondrial structure as measured by previously described methods (Figs 1A and EV1B and C)
Summary
Amyotrophic lateral sclerosis (ALS), which clinically manifests by progressive muscle atrophy and paralysis, is a fatal neurodegenerative disease characterized by the death of upper and lower motor neurons (MN; Boillee et al, 2006). The glutamate release inhibitor, riluzole, and recently approved free radical scavenger, edaravone, are the only medications approved by the FDA for ALS, and there remains a strong need for new treatment strategies (Lacomblez et al, 1996; Faes & Callewaert, 2011; Ittner et al, 2015; Hardiman & van den Berg, 2017). Eligibility for edaravone was restricted to patients with a relatively short disease duration and preserved vital capacity, indicating a need for a more encompassing treatment (Hardiman & van den Berg, 2017; Maragakis, 2017; Sawada, 2017). Transactive response (TAR) DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) have been genetically and pathologically linked to ALS; the underlying mechanisms by which these induce ALS pathology and the causal relationship between these events and the death of the motor neurons remain unclear (Mackenzie et al, 2010)
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