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.

KEYWORDS:

• BACHD rat
• calpain
• Hdh^Q111 knock-in mouse
• huntingtin fragments
• Huntington's disease
• mutant huntingtin aggregates
• neurodegeneration
• olesoxime
• polyglutamine diseases
• proteolysis

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful to all collaborators from past and present studies on the potential benefits of olesoxime as a treatment for HD.

Funding

LEC, OR and HPN received grants by the European Union 7^th Framework Program for RTD, Project MitoTarget, Grant Agreement HEALTH-F2-2008-223388, and JJW was funded by the Baden-Wuerttemberg Foundation, Research Grant Number P-BWS-SPII/3-08.