Investigating Motor Neuron Disease in Spinocerebellar Ataxia, Type1

研究脊髓小脑共济失调 1 型运动神经元疾病

• 批准号: 10733124
• 负责人: James P Orengo
• 金额: $ 54.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733124
• 关键词: Abnormal coordination; Address; Affect; Area; Ataxia; Behavioral; Behavioral Assay; Brain Stem; Breathing; CAG repeat; Cell Culture Techniques; Cell Nucleus; Cells; Cerebellar degeneration; Cessation of life; Deglutition; Denervation; Development; Disease; Disease Progression; Dissociation; Electrophysiology (science); Family; Functional disorder; Genetic Epistasis; Genetic Transcription; Goals; Health; Histology; Impairment; Individual; Intervention; Investigation; Investments; JUN gene; Knowledge; Lead; Life; LoxP-flanked allele; MAPK8 gene; Mediating; Modeling; Molecular; Morphology; Motor Neuron Disease; Motor Neurons; Mus; Muscle Weakness; Muscular Atrophy; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Nuclear; Pathogenicity; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Phosphotransferases; Play; Process; Proteins; Respiration Disorders; Respiratory Failure; Risk; Role; Secondary to; Shortness of Breath; Signal Transduction; Skeletal Muscle; Sorting; Spinal Cord; Spinocerebellar Ataxias; Symptoms; Tissues; Type 1 Spinocerebellar Ataxia; astrogliosis; behavioral phenotyping; brain cell; cell type; deep sequencing; effective therapy; experimental study; in vivo; inhibitor; innovation; interest; mRNA sequencing; motor neuron degeneration; mouse model; neuron loss; neuronal cell body; novel; novel therapeutics; overexpression; polyglutamine; premature; respiratory; response; skeletal muscle wasting; transcriptome sequencing; transcriptomics

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia due to cerebellar degeneration, followed by progressive degeneration and premature death. Substantial effort has been invested in determining the molecular mechanisms that lead to cerebellar degeneration. This is largely due to the fact that impairment of these neurons leads to the first symptoms identified in SCA1 patients. However, loss of cerebellar neurons alone does not account for the muscle weakness and respiratory failure, which characterize SCA1 progression, and promote premature death. This knowledge gap prompts fundamental questions about the pathogenic mechanism of premature death. SCA1 is caused by the expansion of CAG repeats encoding polyglutamines (polyQ) in the ATAXIN1 (ATXN1) protein. The polyQ ATXN1 accumulates in neurons forming nuclear aggregates ultimately leading to neuronal cell death. Of particular interest to the Orengo lab is the role motor neurons play in SCA1. These neurons control skeletal muscle activity, and when diseased, lead to skeletal muscle wasting, weakness, breathing dysfunction, swallowing difficulties and an inability to safely clear the airway, all of which predispose to respiratory complications leading to premature death. Dr. Orengo and his team hypothesize that motor neuron dysfunction in SCA1 is the main driver of premature death and that the mechanisms leading to motor neuron degeneration in SCA1 are different than those involved in cerebellar neuron degeneration. This distinction may be critical in the development of novel therapeutics that address other affected cell types than just cerebellar neurons. Using a cadre of SCA1 mouse models, the Orengo lab will be able to selectively turn on or off the expression of toxic polyQ ATXN1 in motor neurons and assess the molecular and behavioral changes that follow. Specifically, the goals of this proposal are the following. (1) Assess whether expression of polyQ ATXN1 in motor neurons is necessary for premature death in a conditional mouse model of SCA1. (2) Determine the earliest, mid and late transcriptomic changes in motor neurons secondary to autonomous and non-cell-autonomous polyQ ATXN1 expression. This investigation utilizes an innovative in vivo approach, with dissociated motor neurons from the spinal cords of mice, sorting their nuclei based on a fluorescent marker, and then deep sequencing the mRNA molecules present. (3) Explore the role of the master transcriptional regulator Mdfi in a SCA1 mouse model and ascertain its affect upon the JNK/Jun signaling cascade. Dr. Orengo’s proposed study is significant because it will shed new light on the role motor neuron disease plays in SCA1, as well as what pathways are triggered within these neurons that lead to their degeneration. Understanding these mechanisms will be crucial for developing more effective therapies that address muscle weakness and premature death in SCA1 patients.

脊髓小脑性共济失调1型(SCA1)是一种以进行性为特征的破坏性神经退行性疾病。 由小脑变性引起的共济失调，随后是进行性变性和过早死亡。相当可观 人们一直致力于确定导致小脑变性的分子机制。这是 这在很大程度上是因为这些神经元的损伤会导致SCA1患者出现首批症状。 然而，仅有小脑神经元的丧失并不能解释肌肉无力和呼吸衰竭， 这是SCA1进展的特征，并促进过早死亡。这一知识鸿沟促使人们从根本上 关于过早死亡的致病机制的问题。SCA1是由CAG的扩张引起的 重复编码ATAXIN1(ATXN1)蛋白中的多聚谷氨酰胺(PolyQ)。PolyQ ATXN1在 神经元形成核聚集体，最终导致神经元细胞死亡。奥伦戈人特别感兴趣的事 LAB是运动神经元在SCA1中扮演的角色。这些神经元控制着骨骼肌的活动，当患病时， 导致骨骼肌萎缩、虚弱、呼吸功能障碍、吞咽困难和无法安全 清除呼吸道，所有这些都容易导致呼吸道并发症，导致过早死亡。奥伦戈博士 他的团队假设，SCA1区运动神经元功能障碍是过早死亡的主要原因， SCA1区导致运动神经元变性的机制与小脑不同 神经元变性。这一区别可能对解决其他疾病的新疗法的开发至关重要 受影响的细胞类型不仅仅是小脑神经元。使用一组SCA1小鼠模型，Orengo实验室将 能够选择性地开启或关闭运动神经元中毒性PolyQ ATXN1的表达，并评估其分子水平 以及随之而来的行为变化。具体地说，这项提案的目标如下。(1)评估是否 多聚Q-ATXN1在运动神经元中的表达在条件性死亡的小鼠模型中是必需的 SCA1。(2)测定继发性运动神经元转录的最早、中期和晚期变化。 自主和非细胞自主的PolyQ ATXN1表达。这项研究利用了一种创新的体内 方法，从小鼠脊髓分离运动神经元，根据 荧光标记，然后对存在的mRNA分子进行深度测序。(三)发挥主人翁的作用 转录调控因子MDFI在SCA1小鼠模型中的表达及其对JNK/JUN信号转导的影响 卡斯卡德。奥伦戈博士提出的研究具有重要意义，因为它将为运动神经元的作用提供新的线索 疾病在SCA1中起作用，以及在这些神经元中触发了哪些通路导致其 退化。了解这些机制对于开发更有效的治疗方法至关重要 解决SCA1患者的肌肉无力和过早死亡问题。