The role of Parkin in mitophagy and dopaminergic neuron homeostasis

项目摘要/摘要 散发性和遗传性帕金森病与线粒体有关 功能障碍。特别是，Park基因PINK1和Parkin，已知会导致常染色体隐性遗传 早发性帕金森病与溶酶体介导的线粒体选择性降解有关 降解途径巨噬细胞(MA)，也称为有丝分裂吞噬。鉴于PINK1/Parkin依赖 在无脊椎动物和哺乳动物基于细胞的系统中，有丝分裂是机械特征的，精确的 这些基因在调节哺乳动物大脑中线粒体质量控制方面的作用仍然难以捉摸， PINK1或Parkin的结构性丢失不能有力地概括PD的关键特征或显示有缺陷 啮齿动物大脑中的线粒体处理。在人类遗传学数据和机械论之间建立联系 低阶模型的研究对于理解这些基因的致病本质和它们的致病机制是必不可少的 对线粒体质量控制和帕金森病的贡献。 利用小鼠遗传学、光学荧光监测有丝分裂、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基础上，表明 成年小鼠可诱导的Parkin表达缺失导致运动中左旋多巴反应缺陷 协调和运动，并确定帕金的整体丧失是否会导致多巴胺能神经元- 选择性神经退行性变使人联想到帕金森病。目标1将确定在成年动物中是否存在可诱导的Parkin丢失 导致DA能神经元特异性神经退行性变，导致帕金森病样神经病理和行为， 而Aim 2将使用新创造的有丝分裂报告鼠来确定线粒体更新换代是否导致 已观察到的赤字。目标3将建立在初步观察的基础上，表明基础MA中的补偿基于 结构性Parkin丢失掩盖了Parkin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 并提供了对Parkin和有丝分裂在帕金森病发病机制中的作用的关键见解。

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.