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Published July 26, 2018 | Published
Journal Article Open

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

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.

Additional Information

Data Availability Statement: The raw data for graphs in Figures 1-5 are available at https://figshare.com/s/584ca97ed838e5de3bde, with DOI: 10.6084/m9.figshare.6052007. Competing Interests Statement: The authors have declared that no competing interests exist. Funding: This work was funded by grant A-11059 from the CHDI Foundation (https://chdifoundation.org). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Created:
August 19, 2023
Modified:
October 18, 2023