title: The calpain-suppressing effects of olesoxime in Huntington's disease.
abstract: Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm olesoxime's calpain-suppressing effects and support the therapeutic value of olesoxime for Huntington's disease and other disorders involving calpain overactivation.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jonasz J
authors.initials: JJ
authors.lastname: Weber
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Midea M
authors.initials: MM
authors.lastname: Ortiz Rios
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany; Current institution: QPS Austria, Grambach, Austria.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clemens
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
keywords: BACHD rat; HdhQ111 knock-in mouse; Huntington's disease; calpain; huntingtin fragments; mutant huntingtin aggregates; neurodegeneration; olesoxime; polyglutamine diseases; proteolysis