L20 Olesoxime targets calpain overactivation in models of huntington’s disease

Background A long-term treatment study of BACHD rats with olesoxime, a mitochondria-targeting drug, revealed beneficial effects on specific behavioural and neuropathological phenotypes. On the molecular level, olesoxime suppressed the activation of calpains, calcium-dependent cysteine proteases which were associated with cleavage of mutant huntingtin, through a yet unknown mechanism. Aims As calcium dyshomeostasis represents a hallmark of affected neurons in Huntington’s disease and mitochondrial function is essential for the maintenance of calcium levels, olesoxime might exert its calpain suppression by stabilising mitochondrial calcium buffering. By analysing olesoxime’s effects on calpains and calcium homeostasis in further cell and animal models, we sought to elucidate its underlying molecular mode of action. Methods To reproduce the observations made in our BACHD rats, we treated a second animal model of Huntington’s disease, the HdhQ111 knock-in mouse, with olesoxime. For a more precise investigation of olesoxime’s molecular function, we utilised cell models and examined cell viability, calpain activation and calcium buffering capacity after drug treatment. Results We validated the decrease of calpain activation and huntingtin fragmentation by olesoxime treatment in HdhQ111 knock-in mice. Furthermore, cell models showed beneficial effects of olesoxime on cell viability and calcium buffering capacity. Conclusions Our improved understanding of olesoxime’s mode of action can help us to optimise its application as a drug not only in Huntington’s disease but also in other disorders involving calpain overactivation.