The long-term goal of our research is to develop a rational basis for neuroprotective strategies in order to prevent the onset and to slow the progression of Huntington's disease (HD). Increasing evidence suggests that mutant huntingtin (mHtt) and structural and functional abnormalities of mitochondria are involved in neuronal damage and neuronal loss in HD. Several lines of evidence support the involvement of mitochondrial abnormalities in HD progression and pathogenesis: 1) Increased expression levels of the mitochondrial fission genes Drp1 and Fis1 have been found in postmortem tissues from affected brain regions in HD patients and in striatal and cortical tissues from BACHD transgenic mice; 2) Decreased expression levels of the mitochondrial fusion genes Mfn1, Mfn2, and Opa1 have been found in these same affected regions from HD patients and BACHD transgenic mice; 3) Drp1 interacts with mHtt, and this interaction increases as HD progresses; 4) Increased levels of GTPase Drp1 enzymatic activity have been found in HD neurons; and 5) Decreased mitochondrial mass and motility, reduced anterograde axonal transport of mitochondria, and reduced synaptic viability have been found in primary neurons from BACHD transgenic mice. A therapeutic strategy for HD may involve inhibiting excessive mitochondrial fragmentation. Several mitochondrial fission inhibitors have been identified, including the mitochondria division inhibitor Mdivi1. Mdivi1 has been studied using ischemia/reperfusion injury models, renal injury, and oxygen-glucose deprivation. Findings have revealed that Mdivi1 reduces mitochondrial fission and increases mitochondrial fusion, and maintains mitochondrial function and cell survival. In studies of mitochondrial dynamics in an HD-stable striatal cell line that carries 111 polyQ repeats, researchers found reduced levels of fission genes and increased levels of fusion genes in HDQ111 cells treated with Mdivi1. Mdivi1-treated HDQ111 cells also showed increased mitochondrial function and synaptic activity, suggesting that Mdivi1 protects mitochondrial structure and function, and enhances cell survival. The current application seeks to determine whether a partial reduction of Drp1 in neurons from BACHD transgenic mice and HD knockin mice decreases mitochondrial fission and decreases mHtt-induced toxicity; and whether Mdivi1 in neurons from BACHD transgenic mice and HD knockin mice reduces excessive mitochondrial fragmentation and enhances mitochondrial function and synaptic activity. The outcome of this research will be an elucidation of genetic and pharmacological strategies that may reduce excessive mitochondrial fragmentation and increase neuronal survival and synaptic functions in HD-affected neurons.
Mitochondrial dysfunction and oxidative damage are involved in Huntington's disease (HD) pathogenesis. The objectives of the proposed research are to determine whether a partial reduction of the mitochondrial fission protein, Drp1 protects against excessive mutant huntingtin-induced mitochondrial fragmentation, mitochondrial dysfunction, and synaptic toxicities; and to determine whether the mitochondrial division inhibitor, Mdivi 1 protects against mutant huntingtin-induced mitochondrial toxicity and synaptic alterations, and enhances neuronal function and survival in HD-affected neurons.
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