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Mitochondrial fission in Huntington's Disease

亨廷顿病中的线粒体裂变

基本信息

批准号：
9008081
负责人：
Ella R Bossy-Wetzel
金额：
$ 31.38万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9008081
关键词：
ATP Synthesis Pathway Address Affect American Apoptosis Axonal Transport Binding Binding Sites Bioenergetics Buffers Cell Death Cell Survival Cells Cellular biology Chorea Complex Corpus striatum structure Data Defect Dementia Development Disease Dynamin Emotional Energy Metabolism Event Exhibits Family Functional disorder Funding Glutamine Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Homeostasis Human Huntington Disease Huntington gene Hydrolysis Hyperactive behavior In Vitro Inherited Injury Knockout Mice Lead Mediating Mitochondria Mitosis Molecular Conformation Morphology Motor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Patients Phosphorylation Phosphotransferases Physiological Play Post-Translational Protein Processing Process Proteins Role Site Structure Substrate Specificity Synapses Synaptic Transmission System Testing Therapeutic base caregiving cell injury cognitive ability cost cytochrome c effective therapy experience improved in vivo insight knock-down meetings mitochondrial dysfunction mutant neuron loss neurotoxicity novel therapeutics particle polyglutamine progressive chorea research study respiratory self assembly synaptic function targeted treatment three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion of a poly- glutamine (poly-Q) repeats in huntingtin (Htt), a 350 kDa protein. People with HD experience chorea, dementia, and psychiatric disturbances. In HD, long projection neurons of the cortex and striatum degenerate by an unknown mechanism. There is currently no cure or effective treatment for this devastating disease. Neurons depend on mitochondria to provide energy to fuel specialized processes, e.g., synaptic transmission, channel activity, and axonal transport. To meet the constantly changing energy needs of neurons, mitochondria undergo frequent fission and fusion. These dynamic processes stimulate ATP synthesis, maintain Ca2+ homeostasis, and mediate cell survival. However, excessive fission without counterbalancing fusion causes fragmented mitochondrial morphology, neuronal injury, and apoptosis. Fission and fusion is regulated by large conserved GTPases of the dynamin super-family. Dynamin-related protein 1 (DRP1) is required for mitochondrial fission. Under physiological conditions, DRP1 GTPase activity is kept in check. Posttranslational modifications (PTMs) including phosphorylation can activate DRP1. For example, transient DRP1 Ser616 phosphorylation by Cdk1-CyclinB activates mitochondrial fission. There is strong evidence that mitochondrial dysfunction occurs early and plays a causal role in HD. For example, mitochondria from HD patients and HD mice exhibit fragmented morphology, respiratory complex inhibition, diminished Ca2+ buffering capacity, and a sensitized induction towards cytochrome c release and apoptosis. In addition, mutant Htt (mHtt) localizes to mitochondrial fission sites, directly binds DRP1, activates DRP1 GTPase activity, and alters its oligomeric ring-like structure. We have shown that decreasing DRP1 GTPase activity rescues cultured neurons from mHtt-induced excessive mitochondrial fission, axonal transport defects, synaptic injury, and cell death. Persistent Cdk5 activation by p25 and aberrant Cdk5 subcellular localization and substrate specificity also contribute to neurodegeneration. Whether Cdk5-p25 aberrantly phosphorylates DRP1 at Ser616, thereby promoting excessive mitochondrial fission in HD, is unknown. Therefore, the specific questions that will be addressed here are: (1) Does Cdk5-p25 cause DRP1 Ser616 hyperphosphorylation and mitochondrial fission in HD? (2) Does DRP1 Ser616 hyperphosphorylation play a causal role in mHtt-mediated neuronal cell death? (3) By which mechanism does mHtt interaction and Ser616 phosphorylation stimulate DRP1 activity? Results obtained here may provide a mechanistic explanation for DRP1 hyperactivity in neurodegeneration and form the basis for new therapies.

描述（由申请人提供）：亨廷顿氏病（HD）是一种神经退行性疾病，由亨廷顿蛋白（Htt）中聚谷氨酰胺（poly- q）重复序列异常扩增引起，Htt是一种350 kDa蛋白。HD患者会经历舞蹈病、痴呆和精神障碍。在HD中，皮层和纹状体的长投射神经元以一种未知的机制退化。目前还没有治愈或有效治疗这种毁灭性疾病的方法。神经元依赖线粒体提供能量来支持特定的过程，如突触传递、通道活动和轴突运输。为了满足神经元不断变化的能量需求，线粒体经历了频繁的裂变和融合。这些动态过程刺激ATP合成，维持Ca2+稳态，介导细胞存活。然而，没有平衡融合的过度裂变会导致线粒体形态碎片化、神经元损伤和细胞凋亡。裂变和聚变是由动力蛋白超家族的大量保守的gtpase调控的。动力蛋白相关蛋白1 （DRP1）是线粒体分裂所必需的。在生理条件下，DRP1 GTPase活性受到控制。包括磷酸化在内的翻译后修饰（PTMs）可以激活DRP1。例如，Cdk1-CyclinB瞬间磷酸化DRP1 Ser616激活线粒体裂变。有强有力的证据表明，线粒体功能障碍发生早，并在HD中起因果作用。例如，来自HD患者和HD小鼠的线粒体表现出碎片化形态、呼吸复合体抑制、Ca2+缓冲能力减弱以及对细胞色素c释放和凋亡的增敏诱导。此外，突变体Htt （mHtt）定位于线粒体裂变位点，直接结合DRP1，激活DRP1 GTPase活性，改变其寡聚环状结构。我们已经证明，降低DRP1 GTPase活性可以拯救培养的神经元，使其免于mhttt诱导的过度线粒体分裂、轴突运输缺陷、突触损伤和细胞死亡。p25持续的Cdk5激活和异常的Cdk5亚细胞定位和底物特异性也有助于神经退行性变。Cdk5-p25是否会异常磷酸化DRP1的Ser616位点，从而促进HD患者线粒体过度分裂，目前尚不清楚。因此，这里要解决的具体问题是：(1)Cdk5-p25是否导致HD患者DRP1 Ser616过磷酸化和线粒体裂变？(2) DRP1 Ser616过度磷酸化是否在mhtt介导的神经元细胞死亡中起因果作用？(3) mHtt相互作用和Ser616磷酸化刺激DRP1活性的机制是什么？本研究的结果可能为DRP1在神经退行性疾病中的高活性提供了机制解释，并为新疗法提供了基础。