Role of mitochondria in neurodegenerative diseases

线粒体在神经退行性疾病中的作用

• 批准号: 10688932
• 负责人: Richard James Youle
• 金额: $ 171.83万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688932
• 关键词: Age; Animal Model; Autophagocytosis; Autophagosome; Biological; Cells; Cellular biology; Collaborations; Cytosol; DNA; Defect; Drosophila melanogaster; Excision; Genetic Screening; German population; Golgi Apparatus; Idiopathic Parkinson Disease; Immune signaling; Immunity; Impairment; Inflammation; Inflammatory; Interferon Type I; Knock-out; Link; Lipids; Locomotion; Mammalian Cell; Mediating; Membrane; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morphology; Motor; Mus; Muscle; Mutate; Mutation; NF-kappa B; Natural Immunity; Neurodegenerative Disorders; Neurons; PINK1 gene; Parkin; Parkinson Disease; Pathology; Pathway interactions; Patients; Penetrance; Persons; Phenotype; Phosphotransferases; Posture; Quality Control; RNA interference screen; Role; Signal Transduction; Testing; Wing; Work; aged; cohort; cytokine; dopaminergic neuron; fly; gene product; in vivo; innate immune function; loss of function; man; mitochondrial DNA mutation; mutant; neuroprotection; novel; prevent; recruit; response; sensor; small molecule libraries; ubiquitin-protein ligase; whole genome

We have explored the role of mitochondria in Parkinson's disease (PD). At least two gene products mutated in familial PD, PINK1 and Parkin, are now known to mediate autophagic removal of defective mitochondria suggesting that one cause of PD is an impairment of mitochondrial quality control. PINK1 is a kinase located on mitochondria whereas Parkin is an E3 ubiquitin ligase normally located in the cytosol. Upon mitochondrial damage Pink1 recruits cytosolic Parkin to mitochondria to mediate mitophagy revealing a cell biology pathway in mammalian cells where Pink1 works upstream of Parkin. PINK1 acts as a sensor of mitochondria function and Parkin induced the elimination of those damaged mitochondria. An animal model that accumulates mitochondrial DNA mutations corroborates the model that Parkin mediates quality control and rescues neurons from damaged mitochondria. We preformed full genome RNAi screens to identify gene products participating in PINK1 recruitment of Parkin to mitochondria and Parkin stimulation of autophagosome engulfment of mitochondria. 1) The genetic screens led us to identify a strong inflammatory phenotype in both Parkin-/- and PINK1-/- mice when crossed with Mutator mice, which accumulate mitochondrial DNA mutations with age. This inflammation is completely rescued by concurrent loss of STING, a central regulator of the type I Interferon response to cytosolic DNA. The loss of DA neurons from the SNc and the motor defect observed in aged Parkin-/-; Mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. In collaboration with a leading German group with large cohorts of PINK1 and Parkin mutant PD patients we discovered that people with biallelic Parkin mutations also display elevated circulating cytokines at levels higher than either healthy controls or those with idiopathic PD. Furthermore, these biallelic Parkin and PINK1 patients had higher circulating levels of mitochondrial DNA than either healthy controls or idiopathic PD patients. These results support the model that PINK1- and Parkin-mediated mitophagy restrains innate immunity as a way to prevent PD. 2) In contrast to mice and man, recessive mutations in Parkin in Drosophila melanogaster display severe physical and locomotion defects caused by excess mitochondria damage, leading to muscle defects and progressive degeneration of dopaminergic neurons. Innate immunity pathways including STING and NF-kB pathways are conserved in flies, however, the role of innate immune signaling in Pink1/Parkin mutant fly pathology has not been established. We found the conserved immunity regulator STING mediates the Parkin loss of function phenotypes. Two genetically independent STING and Parkin double knockout strains were generated. Deletion of STING with significantly reduces the penetrance of the major Parkin null fly phenotypes including flight muscle defects, wing posture, and climbing ability. Surprisingly, the underlying mitochondria morphology defects in Parkin mutant flies were also suppressed in these double mutant lines. 3) We explored how STING, functioning downstream of mitochondrial damage and mtDNA release into the cytosol, activates innate immunity. We discovered a new and unanticipated function of STING in activating the lipidation of LC3, which is classically thought to be linked to double membrane autophagosomes. Instead of inducing autophagy as had been the dominant model, we found STING lipidates LC3 onto single membrane Golgi associated membranes. The innate immune function of this novel step in STING activity is being explored by us and others.

我们探讨了线粒体在帕金森病（PD）中的作用。家族性帕金森病中至少有两个突变的基因产物PINK1和Parkin介导有缺陷线粒体的自噬清除，这表明帕金森病的一个原因是线粒体质量控制受损。PINK1是一种位于线粒体上的激酶，而Parkin是一种通常位于细胞质中的E3泛素连接酶。在线粒体损伤时，Pink1将细胞质内的Parkin招募到线粒体中介导线粒体自噬，揭示了哺乳动物细胞中Pink1在Parkin上游起作用的细胞生物学途径。PINK1作为线粒体功能的传感器，Parkin诱导这些受损线粒体的消除。积累线粒体DNA突变的动物模型证实了Parkin介导质量控制并从受损的线粒体中拯救神经元的模型。我们进行了全基因组RNAi筛选，以鉴定参与PINK1向线粒体募集Parkin和Parkin刺激线粒体自噬体吞噬的基因产物。