Functional consequences of HSPB1 mutations that result in motor neuron disease

HSPB1 突变导致运动神经元疾病的功能后果

• 批准号: 8731982
• 负责人: Stephen J. Kolb
• 金额: $ 18.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731982
• 关键词: Affect; Animals; Bacterial Artificial Chromosomes; Biological Assay; Biological Models; Biology; Cell Culture Techniques; Cells; Cellular Stress; Cessation of life; Clinical; Data; Development; Distal; Elements; Ensure; Environment; Genes; Goals; HSPB1 gene; Heat shock proteins; Infection; Inflammatory; Inherited; Injury; Interferons; Investigation; Lasers; Lead; Measures; Messenger RNA; Microglia; Microscopy; Modeling; Molecular; Molecular Genetics; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle Weakness; Mutant Strains Mice; Mutate; Mutation; Nerve Crush; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathy; Ohio; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Physicians; Play; Prions; Proteins; RNA; RNA Decay; Reporter; Respiratory Failure; Role; Scientist; Series; Testing; Training; Transgenes; Transgenic Animals; Transgenic Mice; Universities; animal model development; cytokine; effective therapy; in vivo; insight; mRNA Decay; motor neuron function; motor neuron injury; mouse model; mutant; nervous system disorder; neuromuscular; neuron loss; neurotoxicity; new therapeutic target; novel; overexpression; promoter; treatment strategy

DESCRIPTION (provided by applicant): Motor neuron diseases (MNDs) are neurodegenerative disorders that cause muscle weakness and often respiratory failure and death. Rapid progress in the molecular genetics of MNDs has revealed at least 22 distinct genes that are expressed in all cells and yet result exclusively in motor neuron (MN) loss when mutated. The small heat shock protein B1 (HSPB1, formerly HSP27) is mutated in patients with hereditary motor neuropathy (HMN). HSPB1 is unique among MND-causing genes in that overexpression of the wild type HSPB1 is known to be neuroprotective in MNs whereas mutations are toxic to MNs. The primary goal of this proposal is to determine the molecular function of HSPB1 that is relevant to motor neuron survival. To do this, we have developed a mouse model of motor neuropathy expresing the most common HSPB1 mutation (R136W) in neurons. We find that HSPB1 mutant mice display a phenotype of mild weakness that mimics HMN. We propose to develop a second line of mice expressing mutant HSPB1 in all cells so that we may distinguish between MN and non-MN contributions to MN injury. The role of non-neuronal cells in the progression of MND is emerging as an important concept and genes expressed by microglia in particular may be important targets in reducing MN loss in MNDs. We hypothesize that animals expressing HSPB1(R136W) in all cells will have a phenotype that is more severe than animals expressing HSPB1(R136W) exclusively in neurons. HSPB1 is required for a specific mRNA decay pathway caled AU-rich element (ARE)-dependent mRNA decay. AU-rich element mRNA decay is a critical mechanism in all cells to control the expression of a select group of mRNAs. Our preliminary data demonstrate that HSPB1(R136W) is defective in this RNA decay pathway, which raises the possibility that ARE-containing mRNAs (normally degraded via this pathway) may play a role in MN pathology. Many of these genes encode proteins such as interferons and inflammatory cytokines which have protective functions during injury and infections, but can be damaging when upregulated. We hypothesize that mRNA levels of ARE-containing mRNAs will be elevated in MNs and microglia expressing mutant HSPB1 compared to wild type HSPB1. To test this, we will directly measure ARE-containing mRNAs in MNs and microglia in mice. The development of these animals and the identification of the molecular function of HSPB1 that is important for MN survival will lead to new therapeutic targets and treatments for patients with HMN and has great potential to advance our understanding of and provide novel treatment strategies for all MNDs.

描述（由申请人提供）：运动神经元疾病（MND）是一种神经退行性疾病，可导致肌肉无力，通常伴有呼吸衰竭和死亡。MND分子遗传学的快速进展揭示了至少22种不同的基因，它们在所有细胞中表达，但在突变时仅导致运动神经元（MN）丢失。小热休克蛋白B1（HSPB1，以前的HSP 27）在遗传性运动神经病（HMN）患者中发生突变。HSPB1在MND引起基因中是独特的，因为已知野生型HSPB1的过表达在MN中具有神经保护作用，而突变对MN是有毒的。该建议的主要目标是确定与运动神经元存活相关的HSPB1的分子功能。为了做到这一点，我们已经开发了一种运动神经病的小鼠模型，其在神经元中表达最常见的HSPB1突变（R136W）。我们发现，HSPB1突变小鼠表现出轻度虚弱的表型，模仿HMN。我们建议开发在所有细胞中表达突变HSPB1的第二系小鼠，以便我们可以区分MN和非MN对MN损伤的贡献。非神经元细胞在MND进展中的作用正在成为一个重要的概念，特别是小胶质细胞表达的基因可能是减少MND中MN丢失的重要靶点。我们假设在所有细胞中表达HSPB1（R136W）的动物将具有比仅在神经元中表达HSPB1（R136W）的动物更严重的表型。HSPB1是一种特异性的mRNA衰变途径，称为富含AU元件（ARE）依赖性mRNA衰变。富含AU的元件mRNA衰变是所有细胞中控制一组选定mRNA表达的关键机制。我们的初步数据表明，HSPB1（R136W）在这种RNA衰变途径中是有缺陷的，这提高了含ARE的mRNA（通常通过这种途径降解）可能在MN病理中发挥作用的可能性。这些基因中的许多编码蛋白质，如干扰素和炎性细胞因子，其在损伤和感染期间具有保护功能，但当上调时可能具有破坏性。我们假设，与野生型HSPB1相比，表达突变型HSPB1的MN和小胶质细胞中含有ARE的mRNA的mRNA水平将升高。为了测试这一点，我们将直接测量小鼠MN和小胶质细胞中含有ARE的mRNA。这些动物的发展和对HSPB1分子功能的鉴定对MN存活至关重要，这将为HMN患者带来新的治疗靶点和治疗方法，并有很大的潜力促进我们对所有MND的理解并提供新的治疗策略。

项目成果

Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice.

• DOI: 10.1016/j.nbd.2012.03.035
• 发表时间: 2012-08
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Srivastava AK;Renusch SR;Naiman NE;Gu S;Sneh A;Arnold WD;Sahenk Z;Kolb SJ
• 通讯作者: Kolb SJ

Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.

用于针对小儿疾病的脊髓，大脑和周围组织的大物种中的全身基因递送。

• DOI: 10.1038/mt.2011.157
• 发表时间: 2011-11
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy

Spliceosomal small nuclear ribonucleoprotein biogenesis defects and motor neuron selectivity in spinal muscular atrophy.

脊髓性肌萎缩症中剪接体小核核糖核蛋白生物发生缺陷和运动神经元选择性。

• DOI: 10.1016/j.brainres.2012.02.051
• 发表时间: 2012
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Workman,Eileen;Kolb,StephenJ;Battle,DanielJ
• 通讯作者: Battle,DanielJ