Mitochondrial DNA and Ape1 in Huntington's Disease

亨廷顿病中的线粒体 DNA 和 Ape1

• 批准号: 9314641
• 负责人: Sylvette Ayala-Pena
• 金额: $ 29.57万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314641
• 关键词: Affect; Age; Aging; Base Excision Repairs; Bioenergetics; Biological Assay; Brain; Cells; Confocal Microscopy; Corpus striatum structure; DNA Repair; Detection; Development; Exhibits; Genes; Goals; Histology; Human; Huntington Disease; Huntington gene; Intervention; Knock-in Mouse; Lesion; Maintenance; Measures; Mediating; Mitochondria; Mitochondrial DNA; Modification; Motor; Mus; Mutation; Nerve; Nerve Degeneration; Neuropathogenesis; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Performance; Pharmacology; Play; Production; Publications; Research; Role; Site; Small Interfering RNA; Source; Staining method; Stains; Synapses; Synaptosomes; Testing; United States National Institutes of Health; age effect; age related; aged; base; disease phenotype; endonuclease; experimental study; extracellular; in vitro Model; in vivo; insight; mitochondrial dysfunction; mouse model; mutant; neuronal survival; novel; oxidative damage; prevent; public health relevance; repaired; respiratory; transcription factor

 DESCRIPTION (provided by applicant): Substantial evidence suggests that oxidative stress and mitochondrial dysfunction may play a role in neurodegeneration associated with HD. However, the precise mechanism(s) by which mutant huntingtin (htt) causes mitochondrial dysfunction remain largely unknown. We recently demonstrated a regulatory role of Ape1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, on mitochondrial function. Thus, our main objective is to determine the mechanisms of Ape1-mediated mitochondrial dysfunction in the context of mutant htt. This proposal will test the hypothesis that mutant htt, in combination with age-related effects, mediates mitochondrial dysfunction and neurodegeneration by targeting Ape1, which in turn results in deficient repair of mtDNA. We propose to test our hypothesis using a combination of in vivo and in vitro models of HD and directly test our hypothesis by determining if: 1) age-related changes in Ape1 synaptic nerve terminals contribute to mtDNA damage, mitochondrial dysfunction and neurodegeneration in HD and 2) what mechanism(s) might trigger Ape1-associated mitochondrial dysfunction in the context of the htt mutation. This study is likely to provide insight into a possible regulatory mechanism of Ape1 in mutant htt-induced mt dysfunction and neurodegeneration.