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Unraveling the mechanisms of motor neuron degeneration if Spinocerebellar Ataxia, type 1

揭示 1 型脊髓小脑共济失调运动神经元变性的机制

基本信息

批准号：
9757831
负责人：
James P Orengo
金额：
$ 18.94万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757831
关键词：
Address Affect Age Alternative Splicing Amyotrophic Lateral Sclerosis Astrocytes Ataxia Autopsy Brain Stem Breathing CAG repeat Cell Death Cells Cerebellar Ataxia Cerebellar degeneration Cervical spinal cord structure Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cre-LoxP DNA cassette Data Deglutition Disease Electromyography Enterobacteria phage P1 Cre recombinase Etiology Event Face Functional disorder Genes Genetic Glutamine Goals Histology Human Individual Introns Knock-in Knowledge Lead Life LoxP-flanked allele Maps Measures Modeling Molecular Morphology Motor Motor Neurons Motor Pathways Movement Mus Muscle Muscle Fibers Muscle Weakness Muscular Atrophy Neurodegenerative Disorders Neuromuscular Diseases Neurons Pathogenesis Pathogenicity Pathology Phenotype Plethysmography Population Proteins Pulmonary function tests Purkinje Cells RNA Research Respiratory Diaphragm Respiratory Failure Respiratory physiology Scientist Secondary to Structure Supportive care Time Tongue Training Type 1 Spinocerebellar Ataxia Work cell type end stage disease hypoglossal nucleus improved insight motor neuron degeneration mouse model novel polyglutamine premature protein TDP-43 protein protein interaction spasticity tool

项目摘要

PROJECT SUMMARY/ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia from cerebellar degeneration. Death typically occurs by the third to sixth decade of life. While the hallmark of SCA1 is loss of motor coordination or ataxia, at the end stage of disease premature death results from complications secondary to bulbar dysfunction, including swallowing difficulties and breathing dysfunction. In SCA1, disease is caused by expansion of CAG repeats encoding poly-glutamine (polyQ) in ATAXIN1 (Atxn1). Substantial effort has been invested in determining the molecular mechanism leading to cerebellar degeneration, specifically Purkinje cell death, from polyQ expanded Atxn1. This is largely due to the fact that Purkinje cells seem to be the first neurons affected in SCA1 and they are most vulnerable to the pathogenic sequelae of expanded polyQ Atxn1. However, loss of Purkinje cells does not account for the bulbar dysfunction phenotype, which ultimately causes premature death. I hypothesize that motor neuron degeneration is responsible for bulbar dysfunction in SCA1. Further supporting this hypothesis is SCA1 autopsy data showing marked loss of motor neurons in the brainstem. In 2002 our lab developed a pivotal mouse model for SCA1 recapitulating the major human features of disease with robust face and construct validity. In this model, designated Atxn1-154Q, 154 CAG repeats were knocked into the endogenous mouse Atxn1 gene locus. Upon joining the Zoghbi lab, with my clinical expertise in neuromuscular diseases, I made the exciting observation that these mice display overt signs of motor neuron degeneration. In particular I noted significant muscle wasting, breathing abnormalities and spasticity by 24 weeks of age. The goals of this proposal are to examine motor neurons in Atxn1-154Q mice functionally, morphologically and molecularly in order to better understand what causes their degeneration and to establish these mice as an ideal model to study motor neuron degeneration in SCA1.

项目概要/摘要脊髓小脑共济失调 1 型 (SCA1) 是一种破坏性神经退行性疾病，其特征是进行性小脑变性引起的共济失调。死亡通常发生在生命的第三个至第六个十年。虽然 SCA1的标志是运动协调性丧失或共济失调，在疾病末期导致过早死亡延髓功能障碍继发的并发症，包括吞咽困难和呼吸功能障碍。在 SCA1 中，疾病是由 ATAXIN1 中编码聚谷氨酰胺 (polyQ) 的 CAG 重复序列扩增引起的（Atxn1）。人们投入了大量的精力来确定导致小脑的分子机制 PolyQ 扩展的 Atxn1 导致退化，特别是浦肯野细胞死亡。这很大程度上是由于以下事实：浦肯野细胞似乎是 SCA1 中第一个受影响的神经元，它们最容易受到致病性的影响扩展的polyQ Atxn1的后遗症。然而，浦肯野细胞的损失并不能解释延髓功能障碍表型，最终导致过早死亡。我推测运动神经元变性是导致 SCA1 延髓功能障碍。 SCA1 尸检数据进一步支持了这一假设脑干运动神经元明显丧失。 2002 年，我们的实验室开发了 SCA1 的关键小鼠模型具有强大的表面和结构效度来概括疾病的主要人类特征。在这个模型中，命名为 Atxn1-154Q，154 个 CAG 重复序列被敲入内源性小鼠 Atxn1 基因位点。之上加入佐格比实验室，凭借我在神经肌肉疾病方面的临床专业知识，我做出了令人兴奋的观察这些小鼠表现出明显的运动神经元变性迹象。我特别注意到显着的肌肉 24 周龄时出现消瘦、呼吸异常和痉挛。该提案的目标是审查从功能、形态和分子角度对 Atxn1-154Q 小鼠的运动神经元进行研究，以便更好地理解是什么导致了它们的退化，并将这些小鼠建立为研究运动神经元的理想模型 SCA1 变性。