The role of Parkin in selective dopamine neuronal degeneration

Parkin在选择性多巴胺神经元变性中的作用

基本信息

批准号：
8643298
负责人：
JOHN L GOUDREAU
金额：
$ 28.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643298
关键词：
Acute Address Affect Animal Model Autophagosome Cell Death Cell Survival Chronic Complex Data Dopamine Dose Equilibrium Event Exposure to Goals Homeostasis Hypothalamic structure In Vitro Injury Knock-out Knockout Mice Link Mediating Mediator of activation protein Messenger RNA Metabolism Methods Midbrain structure Mitochondria Modeling Molecular Morphology Motor Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Neurotoxins Nonpenetrating Wounds Parkinson Disease Pattern Phenotype Play Population Predisposition Process Proteasome Inhibition Protein Biosynthesis Proteins RNA Interference Recombinant adeno-associated virus (rAAV)Recovery Resistance Risk Role Stress Symptoms Time TimeLine Toxic effect Translating Up-Regulation Wild Type Mouse disability dopaminergic neuron in vivo in vivo Model inhibitor/antagonist mitochondrial dysfunction motor impairment multicatalytic endopeptidase complex neuronal survival neurotoxic neurotoxicity novel overexpression oxidative damage parkin gene/protein parkin protein prevent protein degradation protein expression protein misfolding public health relevance research study response stressor synuclein therapy development ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Progressive degeneration of nigrostriatal (NS) dopamine (DA) neurons underlies the motor symptoms of Parkinson's disease (PD) and therapies that slow progression are lacking. Abnormal DA metabolism has been proposed as a mechanism for the selective degeneration of NSDA neurons. All DA neurons, however, are not affected to the same extent in PD. While there is severe loss of midbrain NSDA neurons, the hypothalamic tuberoinfundibular (TI) DA neurons remain intact. A similar pattern of susceptibility can be seen in these DA neuronal populations when they are exposed to mitochondrial complex I inhibitors in vitro and in vivo. Although NSDA and TIDA neurons have a similar initial response to complex I inhibition, only TIDA neurons are able to recover using a mechanism that is dependent on new protein synthesis. Our preliminary data also implicate that parkin is involved in this differential susceptibility since it is markedly upregulated in TIDA, but not NSDA neurons following an acute toxic injury. Parkin is a multifunctional protein that supports normal mitochondrial function, has an E3 ligase that tags misfolded proteins for proteosomal degradation and appears to protect DA neurons from a variety of toxic insults. Parkin also has important proteosome independent functions that could promote DA neuronal survival. The overall goal of this project is to elucidate the parkin-mediated molecular mechanisms that render NSDA neurons sensitive and TIDA neurons resistant to exogenous neurotoxin exposure. We hypothesize that parkin, acting primarily via proteosome-independent mechanisms, protects TIDA neurons and can rescue NSDA neurons from injury induced by a PD relevant pathological stress, mitochondrial complex I inhibition. To address the central hypothesis, rAAV-mediated, spatially restricted manipulation of parkin expression will be performed in wild-type mice and on mice with a parkin null background. The impact of exogenously modulating parkin expression on the TIDA and NSDA neuronal responses to both acute and chronic neurotoxic stress will be assessed to confirm the central role of parkin in allowing DA neurons to recover following an initial insult. Molecular and pharmacological methods will be used to elucidate the initial downstream mediators of the neuroprotective effects of parkin. Despite the observation that a significant portion of DA neurons have been lost at the onset of clinically observable symptoms of PD, it is plausible that there are neurons that are at risk and dysfunctional, but that could recover if provided the necessary machinery for recovery. Since TIDA neurons are unique amongst DA neurons in their ability to recover from an injury induced by a PD relevant pathological stressor, they provide a powerful platform to dissect the parkin-mediated mechanisms of DA neuronal recovery and could yield novel targets for neuroprotective therapy development.

描述（由申请人提供）：黑质纹状体（NS）多巴胺（DA）神经元的进行性变性是帕金森氏病的运动症状（PD）和缺乏缓慢进展的疗法。已提出异常DA代谢是NSDA神经元选择性变性的一种机制。然而，所有DA神经元在PD中并未在相同的程度上受到影响。虽然中脑NSDA神经元严重丧失，但下丘脑结核（Ti）DA神经元仍然完好无损。当这些DA神经元群体暴露于体外和体内线粒体复合物I抑制剂时，可以看到类似的易感性模式。尽管NSDA和TIDA神经元对复杂I抑制具有相似的初始反应，但只有TIDA神经元才能使用依赖于新蛋白质合成的机制恢复。我们的初步数据还暗示，帕金参与了这种差异敏感性，因为它在TIDA中显着上调，但在急性毒性损伤后不具有NSDA神经元。 Parkin是一种支持正常线粒体功能的多功能蛋白质，具有E3连接酶，该连接酶标记错误折叠的蛋白质以用于蛋白质体降解，并且似乎可以保护DA神经元免受各种有毒的侮辱。帕金还具有重要的蛋白质体独立功能，可以促进DA神经元生存。该项目的总体目标是阐明帕克蛋白介导的分子机制，使NSDA神经元敏感和TIDA神经元具有抗外源性神经毒素暴露的抗性。我们假设Parkin主要通过蛋白体非依赖性机制作用，可以保护TIDA神经元，并可以挽救NSDA神经元免受PD相关病理胁迫，线粒体复合物I抑制作用而引起的损伤。为了解决中心假设，将在野生型小鼠和具有parkin null背景的小鼠中进行RAAV介导的对Parkin表达的空间限制操纵。将评估外源调节Parkin表达对TIDA和NSDA神经元反应对急性和慢性神经毒性应激的影响，以确认Parkin在初次侮辱后允许DA神经元恢复的核心作用。分子和药理学方法将用于阐明帕金神经保护作用的初始下游介体。尽管观察到，在临床上可观察到的PD症状时，大部分DA神经元已经丢失，但有些神经元的风险和功能障碍是合理的，但是如果提供必要的恢复机制，则可以恢复。由于TIDA神经元在DA神经元中是独一无二的，其能力从与PD相关的病理压力源造成的损伤中恢复，因此它们提供了一个强大的平台，以剖析DA神经元恢复的Parkin介导的机制，并可能产生神经保护疗法发育的新颖靶标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Liquid chromatographic-electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP+) in discrete regions of murine brain.

DOI：
10.3109/15376516.2010.538753
发表时间：
2011-03
期刊：
Toxicology mechanisms and methods
影响因子：
3.2
作者：
Lehner A;Johnson M;Simkins T;Janis K;Lookingland K;Goudreau J;Rumbeiha W
通讯作者：
Rumbeiha W

Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.

DOI：
10.1016/j.neuro.2012.02.001
发表时间：
2012-06
期刊：
Neurotoxicology
影响因子：
3.4
作者：
Benskey M;Behrouz B;Sunryd J;Pappas SS;Baek SH;Huebner M;Lookingland KJ;Goudreau JL
通讯作者：
Goudreau JL

FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure.

DOI：
10.1016/j.brainres.2016.08.030
发表时间：
2016-10-15
期刊：
Brain research
影响因子：
2.9
作者：
Patterson JR;Kim EJ;Goudreau JL;Lookingland KJ
通讯作者：
Lookingland KJ

The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.

DOI：
10.1016/j.neuro.2014.11.004
发表时间：
2015-01
期刊：
NEUROTOXICOLOGY
影响因子：
3.4
作者：
Benskey, Matthew J.;Manfredsson, Fredric P.;Lookingland, Keith J.;Goudreau, John L.
通讯作者：
Goudreau, John L.