Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

Abstract

Mitochondrial dysfunction manifests in the pathogenesis of Huntington’s disease (HD), a fatal and inherited neurodegenerative disease. Dynamin-related protein 1 (Drp1) is the primary component of mitochondrial fission and becomes hyperactivated in various models of HD. We previously reported that inhibition of Drp1 hyperactivation by P110, a rationally designed peptide inhibitor of Drp1-Fis1 interaction, is protective in the HD R6/2 mouse model, which expresses a fragment of mutant Huntingtin (mHtt). In this study, we expand our work to test the effect of P110 treatment in HD knock-in (zQ175 KI) mice that express full-length mtHtt and exhibit progressive disease symptoms, reminiscent of human HD. We find that subcutaneously sustained treatment with P110 reduces movement deficits of mice. Moreover, the treatment attenuates striatal neuronal loss, microglial hyperactivity and white matter disorganization in zQ175 KI mice. These findings provide an additional line of evidence that inhibition of Drp1 hyperactivation is sufficient to reduce HD-associated neuropathology and behavioral deficits. We propose that manipulation of Drp1 hyperactivation might be a useful strategy to develop therapeutics for treating HD.

Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease

“…Many of the studies currently published that utilize these compounds are in the context of targeting ischemia-reperfusion injury, typically with significant benefits in mitochondrial morphology and function both in vitro and in vivo ( 277 , 282 – 285 , 290 , 388 ). There have also been studies examining the use of p110 and thus the proposed disruption of the Fis1-Drp1 interaction in models of sepsis related complications such as cardiomyopathy and encephalopathy ( 389 ), as well as neurological diseases including Huntington’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease; of which, these studies found significant improvement in pathogenesis and downstream effects of the diseases ( 91 , 354 , 390 – 392 ). These improvements are determined by criteria such as inhibition of excess mitochondrial fission, decreased reactive oxygen species production, improved mitochondrial membrane potential, and decreased apoptosis.…”

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

“…Thus, mHTT‐induced mitochondrial fission may lead to neuronal dysfunction and toxicity in HD patient brains. This hypothesis is supported by investigations in zQ175 HD mice, which showed that inhibition of DRP1 hyperactivity with a peptide reduces behavioural deficits (Zhao et al ). An abnormal interaction between mHTT and DRP1 was also detected in postmortem brains of HD patients (Shirendeb et al ).…”

Temporal Phenotypic Changes in Huntington’s Disease Models for Preclinical Studies

“…This pathologic feature is replicated in R6/1 and R6/2 mouse models through an increase in the reaction to stress and a prolonged corticosterone responses [77,78]. An increase in anxiety-like behavior was also reported in BACHD mice in early disease [59] and at approximately 8 months in zQ175 mice [79]. Whether the reduced descending rod descent time, narrow beam cross time, and initial hyperactivity detected in female N171-82Q are influenced by an altered stress response is unknown.…”