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 由于小脑变性导致共济失调，随后进行性变性和过早死亡。重大的 人们致力于确定导致小脑变性的分子机制。这是 很大程度上是因为这些神经元的损伤导致了 SCA1 患者出现的第一个症状。 然而，仅小脑神经元的丧失并不能解释肌肉无力和呼吸衰竭， 它是 SCA1 进展的特征，并促进过早死亡。这种知识差距促使我们从根本上 关于过早死亡的致病机制的问题。 SCA1是由CAG扩张引起的 ATAXIN1 (ATXN1) 蛋白中重复编码聚谷氨酰胺 (polyQ)。 PolyQ ATXN1 累积在 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 lab 是运动神经元在 SCA1 中发挥的作用。这些神经元控制骨骼肌活动，当患病时， 导致骨骼肌萎缩、虚弱、呼吸功能障碍、吞咽困难以及无法安全地进食 清理呼吸道，所有这些都会导致呼吸道并发症，导致过早死亡。奥伦戈博士 和他的团队假设 SCA1 运动神经元功能障碍是过早死亡的主要原因 导致 SCA1 运动神经元变性的机制与小脑不同 神经元变性。这种区别对于开发解决其他问题的新疗法可能至关重要 受影响的细胞类型不仅仅是小脑神经元。 Orengo 实验室将使用一批 SCA1 小鼠模型 能够选择性地打开或关闭运动神经元中有毒的polyQ ATXN1的表达并评估分子 以及随之而来的行为改变。具体来说，该提案的目标如下。 (1) 评估是否 在条件性小鼠模型中，运动神经元中polyQ ATXN1的表达是过早死亡所必需的 SCA1。 (2) 确定继发性运动神经元的最早、中期和晚期转录组变化 自主和非细胞自主的polyQ ATXN1表达。这项研究利用了创新的体内 方法，从小鼠脊髓中分离出运动神经元，根据 荧光标记，然后对存在的 mRNA 分子进行深度测序。 （三）探索master的作用 SCA1 小鼠模型中的转录调节因子 Mdfi 及其对 JNK/Jun 信号传导的影响 级联。奥伦戈博士提出的研究意义重大，因为它将为运动神经元的作用提供新的线索 疾病在 SCA1 中发挥作用，以及这些神经元内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疗法至关重要 解决 SCA1 患者的肌肉无力和过早死亡问题。