Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat.
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.
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Laura E
LE
Clemens
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Jonasz J
JJ
Weber
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Tanja T
TT
Wlodkowski
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Libo
L
Yu-Taeger
3 Trophos SA., Parc Scientifique de Luminy Case 931, 13288 Marseille Cedex 9, France.
Magali
M
Michaud
4 Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, Roentgenweg 13, 72076 Tuebingen, Germany.
Carsten
C
Calaminus
5 Department of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
Schamim H
SH
Eckert
5 Department of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
Janett
J
Gaca
6 Novartis Institutes for BioMedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland.
Andreas
A
Weiss
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Janine C D
JC
Magg
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Erik K H
EK
Jansson
5 Department of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
Gunter P
GP
Eckert
4 Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, Roentgenweg 13, 72076 Tuebingen, Germany.
Bernd J
BJ
Pichler
3 Trophos SA., Parc Scientifique de Luminy Case 931, 13288 Marseille Cedex 9, France.
Thierry
T
Bordet
3 Trophos SA., Parc Scientifique de Luminy Case 931, 13288 Marseille Cedex 9, France.
Rebecca M
RM
Pruss
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Olaf
O
Riess
1 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany 2 Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany hoa.nguyen@med.uni-tuebingen.de.
Huu P
HP
Nguyen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002783:Cholestenones / Q000097:blood / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D055647:Rats, Transgenic
D002783:Cholestenones; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C522838:olesoxime; D002154:Calpain
Huntington’s disease; calpain; mitochondrial dysfunction; mutant huntingtin aggregates; olesoxime