Huntington's disease (HD) is a devastating inherited neurodegenerative disorder initiated by a pathological expansion of glutamine within the huntingtin protein. Currently there is no effective treatment to slow the progression or to delay the onset of HD, and the disease is invariably lethal. Impaired energy metabolism has been a long-standing hypothesis for the pathogenesis of HD, and understanding the nature of the mutant huntingtin-induced impairments in mitochondrial functions will significantly impact our comprehension of the pathogenetic mechanism in HD and may reveal potential therapeutic targets. This project builds on previous findings from our laboratory and others that have revealed abnormalities in mitochondrial Ca2+ buffering capacity and increased susceptibility to mitochondrial permeability transition (MPT) to be prevalent across several cellular and genetic HD models. However, the exact contribution of this mitochondrial defect to the etiology of HD and its potential therapeutic validity for future drug discovery and development in HD research remain unknown. The overall goal of this project is to determine whether a mitochondrial Ca2+ handling defect is a determining factor in the etiology of HD in order to validate, or rule out, the development of therapeutic interventions that target this molecular mechanism. Our route to target validation hinges on crossing the Hdh150 knock-in mouse model with existing line of cyclophilin D knockout mice, and examine the effect of the genetic ablation of this critical regulator of the mitochondrial Ca2+-uptake capacity on the well characterized motor and neuropathological phenotypes of the HD knock in mice. Cyclophilin D knockout mice have unambiguously demonstrated that mitochondria isolated from these mice have significantly increased Ca2+ buffering capacity and are resistant to MPT induction. We will further characterize the mitochondria Ca2+ handling defect in Hdh150 knock-in mice by determining the onset and extent of this abnormality over the progressive development of the behavioral and neuropathologic phenotypes of this HD model. We will further determine whether the genetic ablation of cyclophilin D increases the stability of brain and non neuronal HD mitochondria against Ca2+ and prevents the increased vulnerability of HD striatal neurons against Ca2+- deregulation mediated by NMDA receptor activation. The results of this """"""""proof-of-concept"""""""" study will help further our understanding of HD neuropathogenesis, and provide fundamental information concerning the validity of the mitochondrial calcium buffering capacity as a rational new therapeutic target in HD. We plan to test our hypothesis and accomplish the objectives of this project by pursuing the following two specific aims:
Specific Aim 1 : To test the hypothesis that increasing the mitochondrial Ca2+-uptake capacity modulates the phenotype and disease progression of the HdhQ150 mouse model of Huntington disease.
Specific Aim 2 : To test the hypothesis that the genetic ablation of cyclophilin D increase the stability of HD mitochondria against Ca2+.
Huntington's disease (HD) is a devastating inherited neurodegenerative disorder initiated by a pathological expansion of glutamine within the huntingtin protein. Currently there is no effective treatment to slow the progression or to delay the onset of HD, and sadly, the disease is invariably lethal. The objectives of the study outlined in our proposal aim to determine whether a mitochondrial Ca2+ handling defect is a determining factor in the etiology of HD in order to validate, or rule out, the development of therapeutic interventions that target this molecular mechanism.
| Dougherty, S E; Hollimon, J J; McMeekin, L J et al. (2014) Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells. Neurobiol Dis 62:160-71 |
| Kumar, Ashish; Kneynsberg, Andrew; Tucholski, Janusz et al. (2012) Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease. Exp Neurol 237:78-89 |
