Characterization of metabolic dysfunction in the BACHD rat model of Huntington disease and therapeutic targeting with olesoxime

Abstract

The current work addresses the characterization of metabolic abnormalities in the BACHD rat and the therapeutic effects of olesoxime treatment. The BACHD rat is a recently established transgenic model of Huntington disease (HD), which expresses full-length human mutant huntingtin (mHTT) with 97 CAG repeats. It is shown here that metabolic dysfunction is a prominent, early feature of the HD-related pathological phenotype in these rats. BACHD rats suffer from growth impairment and obesity due to deficits in energy metabolism. These deficits are traceable during growth and senescence based on altered physiological parameters. It can be concluded that metabolic abnormalities underlie temporal changes, which when considered a general feature of HD, could explain discrepancies in the outcomes of earlier studies on metabolic dysfunction in HD patients and animal models. In order to therapeutically address metabolic dysfunction in the BACHD rat, a long-term treatment study with the mitochondria-targeting, neuroprotective compound olesoxime was conducted. Although olesoxime did not influence the growth deficit and development of obesity in the BACHD rat, it revealed a positive influence on mitochondrial function and specific behavioral and neuropathological phenotypes. It is suggested that these benefits resulted from improved mitochondrial function and a stabilizing effect on intracellular calcium homeostasis, leading to decreased calcium-dependent activation of the protease calpain-1 and reduced calpain-mediated proteolysis of mutant huntingtin. Further studies with earlier start of olesoxime treatment could help to understand why the compound only exerted selective beneficial effects in the BACHD rat, and to provide further insight into the mechanism of action.