Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat.

Abstract

Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of olesoxime. Our findings suggest that olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of olesoxime as a therapeutic for Huntington's disease.

• Authors: Laura E Clemens, Jonasz J Weber, Tanja T Wlodkowski, Libo Yu-Taeger, Magali Michaud, Carsten Calaminus, Schamim H Eckert, Janett Gaca, Andreas Weiss, Janine C D Magg, Erik K H Jansson, Gunter P Eckert, Bernd J Pichler, Thierry Bordet, Rebecca M Pruss, Olaf Riess, Huu P Nguyen
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 12 Pg. 3632-53 (Dec 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 26490331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Cholestenones
• Htt protein, rat
• Huntingtin Protein
• Mutant Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• olesoxime
• Calpain

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism, pathology)
• Calpain (antagonists & inhibitors, metabolism)
• Cholestenones (blood, metabolism, pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Huntingtin Protein
• Huntington Disease (drug therapy, enzymology, genetics, metabolism)
• Male
• Mitochondria (drug effects, metabolism)
• Mutant Proteins (chemistry, genetics, metabolism)
• Mutation
• Nerve Tissue Proteins (chemistry, genetics, metabolism)
• Nuclear Proteins (chemistry, genetics, metabolism)
• Proteolysis (drug effects)
• Rats
• Rats, Transgenic