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.

项目摘要/摘要 1型脊髓脑性共济失调（SCA1）是一种毁灭性神经退行性疾病，其特征是进行性疾病小脑变性的共济失调。死亡通常发生到生命的第三到第六十年。而 SCA1的标志是运动协调或共济失调的丧失，在疾病过早死亡结果的结束阶段从继发性到鳞茎功能障碍的并发症，包括吞咽困难和呼吸障碍。在SCA1中，疾病是由编码多谷氨酰胺（PolyQ）在ataxin1中的CAG重复膨胀引起的（ATXN1）。已经在确定导致小脑的分子机制方面投入了大量努力来自PolyQ的退化，特别是Purkinje细胞死亡，扩展了ATXN1。这主要是由于 Purkinje细胞似乎是SCA1影响的第一个神经元，它们最容易受到致病性的影响扩展的Polyq ATXN1的后遗症。但是，purkinje细胞的损失不能解释鳞茎功能障碍表型，最终导致过早死亡。我假设运动神经元变性是负责SCA1中的灯泡功能障碍。 SCA1尸检数据显示了进一步支持此假设脑干中运动神经元的明显丧失。 2002年，我们的实验室开发了SCA1的关键小鼠模型以坚固的面部和构造有效性概括疾病的主要人类特征。在这个模型中，指定为ATXN1-154Q，将154个CAG重复击中到内源性小鼠ATXN1基因基因座中。之上加入Zoghbi实验室，凭借我在神经肌肉疾病方面的临床专业知识，我进行了令人兴奋的观察这些小鼠显示出运动神经元变性的明显迹象。特别是我注意到重要的肌肉浪费，呼吸异常和痉挛到24周龄。该提议的目标是检查 ATXN1-154Q小鼠的运动神经元在功能，形态和分子上以更好地理解是什么导致它们的变性并确定这些小鼠作为研究运动神经元的理想模型 SCA1的变性。