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，是由亨廷顿蛋白（HTT）中聚谷氨酰胺（Poly-Q）重复异常扩张引起的，这是一种350 kDa蛋白。具有高清的人会经历舞蹈，痴呆症和精神病患者。在HD中，皮质和纹状体的长投影神经元通过未知机制退化。目前尚无治愈或有效治疗这种毁灭性疾病。神经元依靠线粒体为燃料专业过程提供能量，例如突触传递，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，线粒体会经常进行裂变和融合。这些动态过程刺激ATP合成，维持Ca2+稳态并介导细胞存活。但是，过度裂变而不平衡融合会导致线粒体形态，神经元损伤和凋亡。裂变和融合受动力蛋白超家族的大量保守GTPase调节。线粒体裂变需要动力蛋白相关的蛋白1（DRP1）。在生理条件下，DRP1 GTPase活性受到检查。包括磷酸化在内的翻译后修饰（PTM）可以激活DRP1。例如，CDK1-CYCLINB瞬时DRP1 Ser616磷酸化激活了线粒体裂变。有强有力的证据表明线粒体功能障碍发生早期发生，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的形态，呼吸复合物抑制作用，CA2+缓冲能力降低以及对细胞色素C释放和凋亡的敏感诱导。此外，突变HTT（MHTT）定位于线粒体裂变位点，直接结合DRP1，激活DRP1 GTPase活性，并改变其寡聚环状结构。我们已经表明，降低DRP1 GTPase活性从MHTT诱导的过度线粒体裂变，轴突转运缺陷，突触损伤和细胞死亡中挽救了培养的神经元。 P25和异常CDK5亚细胞定位和底物特异性的持续CDK5激活也有助于神经变性。 CDK5-P25是否在Ser616处异常磷酸化DRP1，从而促进HD中的线粒体裂变过多。因此，此处将要解决的具体问题是：（1）CDK5-P25是否导致HD中的DRP1 Ser616高磷酸化和线粒体裂变？（2）DRP1 Ser616过度磷酸化在MHTT介导的神经元细胞死亡中起因果作用吗？（3）MHTT相互作用和Ser616磷酸化刺激DRP1活性？此处获得的结果可以为神经变性中的DRP1多动症提供一个机械解释，并构成了新疗法的基础。