Removal of the Mitochondrial Fission Factor Mff Exacerbates Neuronal Loss and Neurological Phenotypes in a Huntington's Disease Mouse Model.

Moon Yong Cha,David Chan,Hsiuchen Chen

doi:10.1371/currents.hd.a4e15b80c4915c828d39754942c6631f

Abstract

Objective: Excessive mitochondrial fission has been associated with several neurodegenerative diseases, including Huntington’s disease (HD). Consequently, mitochondrial dynamics has been suggested to be a promising therapeutic target for Huntington’s disease. Mitochondrial fission depends on recruitment of Drp1 to mitochondria, and Mff (mitochondrial fission factor) is one of the key adaptor proteins for this process. Removal of Mff therefore greatly reduces mitochondrial fission. Here we investigate whether removal of Mff can mitigate HD-associated pathologies in HD transgenic mice (R6/2) expressing mutant Htt.Method: We compared the phenotype of HD mice with and without Mff. The mice were monitored for lifespan, neurological phenotypes, Htt aggregate formation, and brain histology.Results: We found that HD mice lacking Mff display more severe neurological phenotypes and have shortened lifespans. Loss of Mff does not affect mutant Htt aggregation, but it accelerates HD pathology, including neuronal loss and neuroinflammation.Conclusions: Our data indicate a protective role for mitochondrial fission in HD and suggest that more studies are needed before manipulation of mitochondrial dynamics can be applied to HD therapy.

Highlights

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disease characterized by progressive, abnormal involuntary movements, rigidity, cognitive decline, and psychiatric symptoms[1 ]
We found that HD mice lacking Mff display more severe neurological phenotypes and have shortened lifespans
Our data indicate a protective role for mitochondrial fission in HD and suggest that more studies are needed before manipulation of mitochondrial dynamics can be applied to HD therapy

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disease characterized by progressive, abnormal involuntary movements (chorea), rigidity, cognitive decline, and psychiatric symptoms[1 ]. There is marked loss of neurons in the caudate nucleus, putamen, and cerebral cortex ,. The disease is caused by a CAG triplet expansion in exon 1 of the HTT (huntingtin) gene[4 ]. This mutation results in an enlarged stretch of polyglutamines in the N-terminus of Htt, with the length correlating with severity of disease. Disease alleles containing 40 or more CAG repeats are fully penetrant ,. There is evidence that Htt http://currents.plos.org/...02r1-removal-of-the-mitochondrial-fission-factor-mff-exacerbates-neuronal-loss-and-neurological-phenotypes-in-a-huntingtons-disease-mouse-model/[10/8/2018 11:12:00 AM]

Methods

Results

Discussion

Conclusion