Determining how neural activity impairs bioenergetics in PD pathogenesis

确定神经活动如何损害 PD 发病机制中的生物能学

基本信息

批准号：
9257471
负责人：
KEN NAKAMURA
金额：
$ 42.27万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257471
关键词：
Affect Age Axon Behavior Bioenergetics Biological Assay Brain Cell Respiration Cells Cessation of life Chronic Complex Consumption Corpus striatum structure Data Defect Dependovirus Dopamine Doxycycline Failure Functional disorder Genetic Glycolysis Goals Impairment In Vitro Individual Lead Measures Methods Midbrain structure Mitochondria Mitochondrial Proteins Mus Mutation Nerve Block Nerve Degeneration Neurons PINK1 gene PTEN-induced putative kinase Parkinson Disease Pathogenesis Pharmacogenetics Play Presynaptic Terminals Preventive treatment Process Production Rattus Research Personnel Respiratory physiology Role Substantia nigra structure Synapses Synaptic Vesicles Testing Toxic effect Translating Work base cohort design designer receptors exclusively activated by designer drugs dopaminergic neuron in vivo innovation insight killings mitochondrial dysfunction myelination nervous system disorder neuron loss postnatal public health relevance relating to nervous system stressor therapeutic target tool vesicular release

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurological disorder in which dopamine (DA) neurons in the brain degenerate and die. A genetic form of PD is caused by mutations in the mitochondrial protein PINK1, which proves that DA neurons are selectively vulnerable to specific mitochondrial stressors. Interestingly, considerable evidence suggests that mitochondrial function is also disrupted in sporadic (rather than genetic) forms of PD, and these changes may also selectively kill DA neurons. So, why are DA neurons susceptible to mitochondrial dysfunction? Because a critical role of mitochondria is to produce energy, many researchers believe that DA neurons are susceptible to energy failure. For example, DA neurons may not be able to produce as much energy or they might require more energy than other types of neurons. Indeed, much of the brain's energy is dedicated to supporting neural activity, and the activity of DA neurons may increase in PD. However, although many believe that energy failure plays a central role in PD pathophysiology, we know remarkably little about energy levels in DA neurons; we don't know if energy failure even occurs in these cells. In order to investigate energy failure in DA neurons, we developed innovative assays to measure ATP and visualize mitochondria in individual neurons. With these methods, we can now test our central hypothesis that DA neurons intrinsically require more energy than other types of neurons to sustain their neural activity, making them particularly susceptible to insults that further increase their energy demands or compromise mitochondrial function. The overall objective of the proposed study is to understand if DA neurons have intrinsic differences in the way they produce or consume energy that make them susceptible to energy failure. We will accomplish these objectives in three specific aims. (1) We will determine if DA neurons have intrinsic deficits in mitochondrial bioenergetic function at the synapse. To do this, we will measure energy production and consumption in individual DA neurons with our newly developed assays to evaluate mitochondrial energy levels in individual synaptic boutons. (2) We will determine if and how loss of the PD protein PINK1 compromises bioenergetic function in DA neurons by determining how losing PINK1 affects these neurons' mitochondrial distribution and function. (3) We will determine if the level of neural activity makes DA neurons even more susceptible to energy failure by assessing their function and death after changing activity levels. Overall, these studies will advance our understanding of if and how energy failure develops in DA neurons, and they will provide insight into how we might therapeutically target energy failure in PD.

描述（由申请人提供）：帕金森病（PD）是一种进行性神经系统疾病，其中大脑中的多巴胺（DA）神经元退化并死亡。PD的遗传形式是由线粒体蛋白PINK1的突变引起的，这证明了DA。神经元选择性地容易受到特定线粒体应激源的影响，大量证据表明，在散发性（而不是遗传性）形式的 PD 中，线粒体功能也会受到破坏，并且这些变化也可能选择性地杀死 DA。那么，为什么 DA 神经元容易受到线粒体功能障碍的影响呢？因为线粒体的一个关键作用是产生能量，因此许多研究人员认为 DA 神经元很容易出现能量衰竭，例如，DA 神经元可能无法产生那么多的能量。事实上，大脑的大部分能量都用于支持神经活动，并且 DA 神经元的活动可能会在 PD 中增加。 PD 病理生理学，我们对此知之甚少DA 神经元中的能量水平；我们不知道这些细胞中是否发生能量衰竭，为了研究 DA 神经元中的能量衰竭，我们开发了测量 ATP 并可视化单个神经元中线粒体的创新方法。现在测试我们的中心假设，即 DA 神经元本质上比其他类型的神经元需要更多的能量来维持其神经活动，使它们特别容易受到进一步增加其能量需求或损害线粒体功能的损伤。这项研究的总体目标是了解。如果 DA 神经元在方式上存在内在差异它们产生或消耗能量，使它们容易出现能量衰竭。我们将通过三个具体目标来实现这些目标：（1）我们将确定 DA 神经元的突触线粒体生物能量功能是否存在内在缺陷。使用我们新开发的测定法来评估单个突触 bouton 中的线粒体能量水平，以评估单个 DA 神经元的能量产生和消耗 (2) 我们将通过确定 PD 蛋白 PINK1 的丢失是否以及如何损害 DA 神经元的生物能量功能。失去 PINK1 如何影响这些神经元的线粒体分布和功能 (3) 我们将通过评估神经活动水平改变后的功能和死亡来确定神经活动水平是否使 DA 神经元更容易受到能量衰竭的影响。总体而言，这些研究将增进我们对 DA 神经元是否以及如何发生能量衰竭的理解，并将为我们如何治疗帕金森病的能量衰竭提供见解。