The role of Parkin in mitophagy and dopaminergic neuron homeostasis

Parkin 在线粒体自噬和多巴胺能神经元稳态中的作用

• 批准号: 10465038
• 负责人: Christopher Joseph Griffey
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465038
• 关键词: Actins; Adult; Age; Autophagocytosis; Behavior; Biochemical; Biology; Brain; Cells; Cre lox recombination system; Data; Defect; Degradation Pathway; Development; Disease; Drosophila melanogaster; Evaluation; Event; Fibroblasts; Financial compensation; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Health; Health system; Homeostasis; Human Genetics; Invertebrates; Knockout Mice; Levodopa; Life; Link; Lysosomes; Maintenance; Mammalian Cell; Masks; Mediating; Mitochondria; Modeling; Monitor; Motor; Movement; Mus; Nature; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Optics; PARK2 gene; PINK1 gene; Parkin; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Protein Biochemistry; Proteomics; Quality Control; Rattus; Reporter; Reporting; Research; Resolution; Rodent; Role; Substantia nigra structure; System; Tamoxifen; Testing; Toxin; Up-Regulation; axonal degeneration; base; behavioral phenotyping; brain cell; combat; dopaminergic neuron; early onset; experimental study; glutamatergic signaling; insight; mature animal; mitochondrial dysfunction; mouse genetics; mouse model; neuropathology; novel therapeutic intervention; stable cell line; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Parkinson disease (PD) of both sporadic and genetic etiologies is associated with mitochondrial dysfunction. In particular, the PARK genes PINK1 and Parkin, which are known to cause autosomal recessive early-onset PD, have been implicated in the selective degradation of mitochondria by the lysosome-mediated degradation pathway macroautophagy (MA), also known as mitophagy. Given that PINK1/Parkin-dependent mitophagy was mechanistically characterized in invertebrate and mammalian cell-based systems, the precise role of these genes in regulating mitochondrial quality control in the mammalian brain has remained elusive, with constitutive loss of PINK1 or Parkin failing to robustly recapitulate key features of PD or show defective mitochondrial handling in the rodent brain. Establishing a link between human genetics data and the mechanistic studies in lower-order models is essential to understand the pathogenic nature of these genes and their contribution to mitochondrial quality control and PD. Using a combination of mouse genetics, optical fluorescent monitoring of mitophagy, protein biochemistry, neuropathology, and behavior, this proposal aims to build upon exciting preliminary data indicating that the inducible loss of Parkin expression in the adult mouse leads to levodopa-responsive defects in motor coordination and movement, and determine if the global loss of Parkin leads to a dopaminergic (DAergic) neuron- selective neurodegeneration reminiscent of PD. Aim 1 will determine if inducible loss of Parkin in the adult animal leads to a DAergic neuron-specific neurodegeneration and resulting PD-like neuropathology and behavior, whereas Aim 2 will use a newly created mitophagy reporter mouse to determine if mitochondrial turnover leads to the observed deficits. Aim 3 will build on initial observations suggesting that compensation in basal MA upon constitutive Parkin loss masks the necessity for Parkin for mitochondrial turnover and the maintenance of central nervous system health. Together, these studies will elucidate mechanisms of mitochondrial quality control in the mammalian brain and provide key insight into the roles of Parkin and mitophagy in the pathogenesis of PD.

项目摘要/摘要 帕金森病（PD）的散发性和遗传性病因与线粒体 功能障碍特别是PARK基因PINK 1和Parkin，它们已知引起常染色体隐性遗传， 早发性PD与溶酶体介导的线粒体选择性降解有关。 降解途径巨自噬（MA），也称为线粒体自噬。PINK 1/Parkin依赖 线粒体自噬在无脊椎动物和哺乳动物细胞为基础的系统中具有机械特征， 这些基因在调节哺乳动物脑中线粒体质量控制中的作用仍然是难以捉摸的， PINK 1或Parkin的组成性缺失未能有力地概括PD的关键特征或表现出缺陷 啮齿动物大脑中的线粒体处理。在人类遗传学数据和机械学之间建立联系 在低阶模型中的研究对于理解这些基因的致病性质及其 有助于线粒体质量控制和PD。 利用小鼠遗传学、光荧光监测线粒体自噬、蛋白质 生物化学，神经病理学和行为学，这项建议旨在建立在令人兴奋的初步数据表明， 成年小鼠中Parkin表达的诱导性缺失导致运动神经元中左旋多巴反应性缺陷， 协调和运动，并确定帕金的整体损失是否导致多巴胺能（DA能）神经元- 选择性神经变性让人联想到帕金森病目的1将确定成年动物中是否存在可诱导的帕金丢失 导致DA能神经元特异性神经变性和导致的PD样神经病理学和行为， 而Aim 2将使用新创建的线粒体自噬报告小鼠来确定线粒体更新是否导致 观察到的缺陷。目标3将建立在初步观察的基础上，初步观察表明， 组成性帕金损失掩盖了帕金对线粒体周转和维持中枢神经系统的必要性。 神经系统健康总之，这些研究将阐明线粒体质量控制的机制， 哺乳动物脑的研究，并提供关键的洞察帕金和线粒体自噬在PD发病机制中的作用。