Regulation of Mitochondrial Function and Motor Neuron Degeneration in SMA

SMA 线粒体功能和运动神经元变性的调节

• 批准号: 9321437
• 负责人: Yongchao Charles Ma
• 金额: $ 31.06万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321437
• 关键词: Acetylation; Affect; Behavioral; Binding Proteins; Biochemical; Biological; Calcium Binding; Cell physiology; Cells; Clinical Trials; Cyclin-Dependent Kinase 5; DNA Sequence Alteration; Deacetylation; Defect; Development; Disease; Functional disorder; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; HDAC5 gene; Human; Infant Mortality; Inherited; Kinesin; Knock-out; Lead; Light; Live Birth; Maps; Mass Spectrum Analysis; Mediating; Microtubules; Mitochondria; Motor; Motor Neurons; Movement; Mus; Mutagenesis; Neurodegenerative Disorders; Outer Mitochondrial Membrane; Oxidative Stress; Pathogenesis; Patients; Phenotype; Phosphorylation; Phosphotransferases; Pilot Projects; Proteins; Quality Control; Regulation; Research; Role; Sampling; Serine; Signal Pathway; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Muscular Atrophy; Testing; Therapeutic; Tissues; effective therapy; in vivo; insight; mitochondrial dysfunction; motor neuron degeneration; mouse model; mutant; nervous system disorder; neuron loss; novel; novel therapeutic intervention; prevent; public health relevance

 DESCRIPTION (provided by applicant): Regulation of Mitochondrial Function and Motor Neuron Degeneration in SMA. Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the degeneration of spinal motor neurons. Although the genetic mutations that lead to SMA have been mapped to the Survival Motor Neuron 1 (SMN1) gene, mechanisms underlying spinal motor neuron degeneration remain largely unknown. Currently, there is no effective treatment for SMA despite ongoing clinical trials. This proposal aims to investigate a novel mechanism regulating mitochondrial functions, and how dysregulation of this mechanism leads to mitochondrial oxidative stress and motor neuron degeneration in SMA. Findings from these studies will have broad implications for understanding neurodegenerative disorders and for developing therapeutic strategies. Using two SMA mouse models and human SMA patient spinal cord samples, we have found that the kinase activity of cyclin-dependent kinase 5 (Cdk5) and its phosphorylation of histone deacetylase 5 (HDAC5) on serine 279 (S279) is significantly increased in motor neurons affected by SMA, leading to increased cytoplasmic localization of HDAC5. We have also observed that HDCA5 deacetylates mitochondrial outer membrane-binding protein Miro, which regulates mitochondrial movement and clearance. Furthermore, we made novel findings that mitochondrial oxidative stress was dramatically increased while mitochondrial movement was reduced in SMA motor neurons. In this proposal, we plan to use a combination of mouse genetic, cell biological and biochemical approaches to investigate how Cdk5-mediated phosphorylation of HDAC5 S279 regulates mitochondrial function and how dysregulation of this mechanism leads mitochondrial oxidative stress and motor neuron degeneration in SMA. Specifically, we will 1) characterize the effects of HDAC5-mediated deacetylation on Miro functions; 2) elucidate the mechanisms by which mitochondrial functions are dysregulated in SMA; 3) investigate the role of Cdk5 signaling pathway in SMA pathogenesis in vivo. Findings from the proposed research will provide insights into mechanisms regulating mitochondrial function, oxidative stress and motor neuron degeneration in SMA. These studies will facilitate the development of new therapeutic strategies for SMA and other neurodegenerative disorders.

 描述(申请人提供)：SMA中线粒体功能和运动神经元变性的调节。脊髓性肌萎缩症(SMA)是导致婴儿死亡的主要遗传原因，其特征是脊髓运动神经元的退化。尽管导致SMA的基因突变已被定位于存活运动神经元1(SMN1)基因，但脊髓运动神经元变性的潜在机制仍很大程度上仍不清楚。目前，尽管正在进行临床试验，但还没有有效的治疗方法。本研究旨在探讨一种新的线粒体功能调控机制，以及该机制的失调如何导致SMA中线粒体氧化应激和运动神经元变性。这些研究的发现将对理解神经退行性疾病和制定治疗策略具有广泛的意义。在两个SMA小鼠模型和人SMA患者脊髓标本中，我们发现SMA影响的运动神经元中细胞周期蛋白依赖性激酶5(CDK5)的活性及其组蛋白脱乙酰基酶5(HDAC5)对丝氨酸279的磷酸化(S279)显著增加，导致HDAC5的胞浆定位增加。我们还观察到HDCA5去乙酰化线粒体外膜结合蛋白MIRO，该蛋白调节线粒体的运动和清除。此外，我们还发现，SMA运动神经元的线粒体氧化应激显著增加，而线粒体运动减少。在这项提议中，我们计划结合小鼠遗传学、细胞生物学和生化方法来研究CDK5介导的HDAC5 S279磷酸化如何调节线粒体功能，以及这一机制的失调如何导致SMA中线粒体氧化应激和运动神经元变性。具体地说，我们将1)研究HDAC5介导的脱乙酰基对MIRO功能的影响；2)阐明SMA中线粒体功能失调的机制；3)探讨CDK5信号通路在SMA体内发病机制中的作用。这项拟议的研究结果将为调控SMA中线粒体功能、氧化应激和运动神经元退化的机制提供见解。这些研究将促进SMA和其他神经退行性疾病的新治疗策略的开发。