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（SCA 1）是一种破坏性的神经退行性疾病，其特征在于进行性 由于小脑变性引起的共济失调，随后是进行性变性和过早死亡。实质性 人们一直在努力确定导致小脑变性的分子机制。这是 这主要是由于这些神经元的损伤导致SCA 1患者中识别的第一症状。 然而，小脑神经元的损失本身并不能解释肌肉无力和呼吸衰竭， 其表征SCA 1进展并促进过早死亡。这种知识差距促使人们从根本上 关于过早死亡的致病机制的问题。SCA 1由CAG扩张引起 ATAXIN 1（ATXN 1）蛋白中编码多聚谷氨酰胺（polyQ）的重复序列。polyQ ATXN 1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SCA 1中发挥的作用。这些神经元控制骨骼肌的活动，当患病时， 导致骨骼肌消耗、虚弱、呼吸功能障碍、吞咽困难和不能安全地 清理呼吸道，所有这些都容易导致呼吸系统并发症，导致过早死亡。奥伦戈医生 他的团队假设SCA 1中的运动神经元功能障碍是过早死亡的主要驱动因素， SCA 1运动神经元变性的机制与小脑运动神经元变性的机制不同， 神经元变性这种区别在开发新的治疗方法中可能是至关重要的， 受影响的细胞类型不仅仅是小脑神经元。使用SCA 1小鼠模型的干部，Orengo实验室将 能够选择性地打开或关闭运动神经元中毒性polyQ ATXN 1的表达，并评估其分子机制。 以及随之而来的行为变化具体而言，本提案的目标如下。(1)评估是否 运动神经元中polyQ ATXN 1的表达是条件性小鼠模型中过早死亡所必需的。 SCA1. (2)确定运动神经元中继发的最早、中期和晚期转录组变化 自主和非细胞自主的polyQ ATXN 1表达。这项研究利用了一种创新的体内 方法，从小鼠脊髓中分离运动神经元，根据细胞核的 荧光标记，然后对存在的mRNA分子进行深度测序。(3)探索大师的角色 转录调节因子Mdfi在SCA 1小鼠模型中的表达，并确定其对JNK/Jun信号传导的影响 级联。Orengo博士提出的这项研究意义重大，因为它将为运动神经元的作用提供新的线索。 疾病在SCA 1中的作用，以及在这些神经元中触发了什么途径，导致它们的 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SCA 1患者的肌无力和过早死亡。