Biology of Parkin and It's Role in Parkinson's Disease

帕金生物学及其在帕金森病中的作用

• 批准号: 8882845
• 负责人: Ted M. Dawson
• 金额: $ 41.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882845
• 关键词: ABL1 gene; Adult; Affinity Chromatography; Alpha-Synuclein transgenic mouse; Amino Acids; Apoptosis; Biogenesis; Biology; Brain; Cells; Cessation of life; Complex; Data; Defect; Due Process; Event; Failure; Funding; Gene Proteins; Genes; Genetic; Genetic Transcription; Goals; Human; Impairment; Investigation; Knock-out; Knockout Mice; Lead; Mammals; Mediating; Methodology; Mitochondria; Modeling; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nodal; Oxidative Stress; Parkin gene; Parkinson Disease; Pathogenesis; Patients; Phosphorylation; Play; Poly Adenosine Diphosphate Ribose; Polymerase; Process; Proteins; Proteomics; Quality Control; RNA; Recommendation; Research; Ribosomes; Role; Signal Transduction; Stable Isotope Labeling; Substantia nigra structure; TNFRSF5 gene; Technology; Therapeutic; Time; Toxic effect; Transcription Repressor/Corepressor; Transgenic Mice; Translating; Ubiquitin-Proteasomal Pathway; Ubiquitination; Up-Regulation; age related; alpha synuclein; base; biological adaptation to stress; c-abl Proto-Oncogenes; deep sequencing; disease-causing mutation; dopaminergic neuron; feeding; insight; loss of function; loss of function mutation; mitochondrial dysfunction; nitrosative stress; overexpression; oxidant stress; parkin gene/protein; prevent; small hairpin RNA; ubiquitin-protein ligase

PROJECT SUMMARY - PROJECT 1: BIOLOGY OF PARKIN AND ITS ROLE IN PARKINSON'S DISEASE Parkinson's disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. Mutations in parkin are the most common cause of autosomal recessive PD. In sporadic PD dopaminergic, oxidative and nitrosative stress as well as c-Abl phosphorylation result in inhibition of parkin. Thus, loss of parkin function is elemental to both familial and sporadic PD. Parkin is an E3 ligase, this loss of function leads to accumulation of the substrates, AIMP2 and PARIS. We have found that AIMP2 expression leads to age dependent DA neurodegeneration due to parthanatos. And PARIS expression may lead to loss of mitochondrial quality control that promotes neurodegeneration. Our hypothesis is that parkin inactivation in sporadic PD by nitrosative/oxidative stress, and c-Abl activation leads to phosphorylation of parkin on Y143 (pY143 parkin) and inactivation followed by the accumulation of parkin substrates, loss of mitochondrial quality control and toxicity. In parallel, α-synuclein is phosphorylated on Y39 (pY39 α-synuclein) resulting in aggregation and subsequent toxicity. Since aggregated α-synuclein can lead to mitochondrial dysfunction it creates a feed forward cycle. Aim 1: One of the unifying features of PD is mitochondrial dysfunction. This aim will explore the inter- relationship of PARIS and mitochondrial dysfunction caused by mutations in parkin. We have shown that PARIS is an important pathophysiologic substrate of parkin in PD that transcriptionally represses PGC-1α a major transcriptional co-activator that regulates mitochondrial biogenesis and mitochondrial oxidant stress responses. Aim 2: Inactivation of parkin results in accumulation of both AIMP2 and PARIS. Expression of either AIMP2 or PARIS is sufficient to promote age dependent DA neurodegeneration. The sequence of events activated by PARIS and AIMP2 will be explored to determine if and how these two proteins interact to initiate the cell death program, parthanatos. Aim 3: We observe pY143 parkin and elevated AIMP2 and PARIS in A53T α-synuclein transgenic mice that raises the question of whether parkin inactivation, PARIS and AIMP2 upregulation and PARP1 activation play a role in α-synuclein induced neurodegeneration? This possibility will be explored with the α-synuclein preformed fibrils (PFFs) model of PD. Aim 4: State-of-the-art technology including deep sequencing and SILAM (stable isotope labeling by amino acids in mammals) will be deployed to identify genes and proteins that are regulated by adult conditional knockout of parkin and their relationship to PARIS induction with the goal of identify nodal points in the signal cascade of neurodegeneration that can provide new targets for the treatment of PD.

项目总结-项目1：帕金森氏病的生物学及其在帕金森氏病中的作用