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

基本信息

  • 批准号:
    8882845
  • 负责人:
  • 金额:
    $ 41.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Ted M. Dawson其他文献

Molecular mediating prion-like α-synuclein fibrillation from toxic PFFs to nontoxic species
分子介导从有毒 PFF 到无毒物种的类朊病毒 α-突触核蛋白纤维颤动
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Longgang Jia;Yuqing Liu;Wenliang Wang;Ying Wang;Haiqing Liu;Fufeng Liu;Rong Chen;Valina L. Dawson;Ted M. Dawson;Fuping Lu;Lei Liu;Yanping Wang;Xiaobo Mao
  • 通讯作者:
    Xiaobo Mao
Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke
PARP 依赖性细胞死亡(Parthanatos):在神经退行性疾病和中风中的机制、调节及治疗前景
  • DOI:
    10.1016/j.bcp.2024.116174
  • 发表时间:
    2024-10-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Liu Yang;Lauren Guttman;Valina L. Dawson;Ted M. Dawson
  • 通讯作者:
    Ted M. Dawson
α-Synuclein pathology as a target in neurodegenerative diseases
α-突触核蛋白病理作为神经退行性疾病的靶点
  • DOI:
    10.1038/s41582-024-01043-w
  • 发表时间:
    2024-11-28
  • 期刊:
  • 影响因子:
    33.100
  • 作者:
    Hyejin Park;Tae-In Kam;Valina L. Dawson;Ted M. Dawson
  • 通讯作者:
    Ted M. Dawson
Preclinical studies and transcriptome analysis in a model of Parkinson’s disease with dopaminergic ZNF746 expression
  • DOI:
    10.1186/s13024-025-00814-3
  • 发表时间:
    2025-02-28
  • 期刊:
  • 影响因子:
    17.500
  • 作者:
    Ji Hun Kim;Sumin Yang;Hyojung Kim;Dang-Khoa Vo;Han-Joo Maeng;Areum Jo;Joo-Heon Shin;Joo-Ho Shin;Hyeon-Man Baek;Gum Hwa Lee;Sung-Hyun Kim;Key-Hwan Lim;Valina L. Dawson;Ted M. Dawson;Jae-Yeol Joo;Yunjong Lee
  • 通讯作者:
    Yunjong Lee
Molecular Mediation of Prion-like α-Synuclein Fibrillation from Toxic PFFs to Nontoxic Species
类朊病毒 α-突触核蛋白纤维化从有毒 PFF 到无毒物种的分子介导
  • DOI:
    10.1021/acsabm.0c00684
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Longgang Jia;Yuqing Liu;Wenliang Wang;Ying Wang;Haiqing Liu;Fufeng Liu;Rong Chen;Valina L. Dawson;Ted M. Dawson;Fuping Lu;Lei Liu;Yanping Wang;Xiaobo Mao
  • 通讯作者:
    Xiaobo Mao

Ted M. Dawson的其他文献

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{{ truncateString('Ted M. Dawson', 18)}}的其他基金

BIOMARKER DISCOVERY AND VALIDATION IN PSP
PSP 中生物标志物的发现和验证
  • 批准号:
    9750090
  • 财政年份:
    2018
  • 资助金额:
    $ 41.31万
  • 项目类别:
Biomarker Discovery and Validation in Parkinson's Disease
帕金森病生物标志物的发现和验证
  • 批准号:
    9269667
  • 财政年份:
    2017
  • 资助金额:
    $ 41.31万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8882841
  • 财政年份:
    2014
  • 资助金额:
    $ 41.31万
  • 项目类别:
Biology of Parkin and Its Role in Parkinson's Disease
帕金生物学及其在帕金森病中的作用
  • 批准号:
    8540519
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
cell Function & Pathophysiology Project
细胞功能
  • 批准号:
    8294095
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
  • 批准号:
    9116479
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
  • 批准号:
    9143805
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
  • 批准号:
    8472291
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
  • 批准号:
    8740577
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
  • 批准号:
    8554394
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:

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