Mechanistic insights of cortical hyperexcitability in ALS

ALS 皮质过度兴奋的机制见解

• 批准号: 10727465
• 负责人: Jie Jiang
• 金额: $ 43.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727465
• 关键词: ALS patients; Adult; Affect; American; Amyotrophic Lateral Sclerosis; Animals; Behavioral; Brain Stem; C9ORF72; Cells; Cessation of life; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Diagnosis; Disease; Enhancers; Etiology; Functional disorder; Gene Delivery; Genes; Genetic; Genetic study; Human; In Vitro; Individual; Interneurons; Intervention; Intrinsic factor; Label; Longevity; Maintenance; Molecular; Motor; Motor Cortex; Motor Neurons; Movement; Mus; Muscle; Muscle Cramp; Muscle Weakness; Muscle fasciculation; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Onset of illness; Paralysed; Parvalbumins; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Play; Quality of life; Reporting; Rodent Model; Role; Specificity; Spinal; Spinal Cord; System; Testing; Therapeutic Intervention; Transgenic Mice; United States; Vertebral column; Viral; experience; gamma-Aminobutyric Acid; genetic approach; hippocampal pyramidal neuron; improved; in vivo Model; insight; knock-down; motor deficit; motor neuron degeneration; mutant; neural; neuron loss; neurophysiology; novel therapeutics; overexpression; pharmacologic; protein TDP-43; receptor; superoxide dismutase 1; therapeutic target; tool; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the loss of upper and lower motor neurons, leading to progressive muscle weakness and paralysis. Many altered molecular and cellular pathways have been implicated in disease pathogenesis. However, determining which are causative remains challenging, and many clinical trials have failed in the last few decades. One explanation for the unsuccessful clinical interventions is the difficulty of rescuing dying motor neurons once death has been triggered, meaning that therapeutic interventions must be implemented early in the disease. Months before clinical onset, ALS patients often experience fasciculations and cramps (i.e., spontaneous and persistent muscle twitching), suggesting increased neural activity and excitability. Indeed, neurophysiological studies in patients and rodent models with ALS-associated genetic mutations have identified that circuit dysfunction, specifically motor cortex hyperexcitability, are among the earliest pathologies. Recently, two studies suggested that upper corticospinal motor neurons (CSMN) in the motor cortex play an essential role in the low motor neuron death of transgenic mice expressing human SOD1 mutations. We thus hypothesize that CSMN hyperexcitability might drive ALS pathogenesis. We propose to utilize recently developed enhancer-driven viral tools that allow cell-specific targeting to 1) perform cutting-edge chemogenetics to modulate neuronal activity to determine whether dampening CSMN hyperexcitability in the late pre-symptomatic stage can mitigate ALS- related behavioral and pathological deficits in SOD1G93A mice, and 2) identify cell-specific altered molecular pathways leading to motor cortex hyperexcitability. This study has significant implications in developing therapeutics targeting this early clinical abnormality in ALS patients.

项目总结/摘要 肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种由上皮层神经元缺失引起的破坏性神经退行性疾病， 和较低的运动神经元，导致进行性肌肉无力和瘫痪。许多改变的分子和 细胞途径与疾病发病机制有关。然而，确定哪些是因果关系， 仍然具有挑战性，在过去的几十年里，许多临床试验都失败了。的一个解释 不成功的临床干预是一旦死亡， 这意味着治疗干预必须在疾病早期实施。个月前 在临床发病时，ALS患者经常经历肌束震颤和痉挛（即，自发性和持续性 肌肉抽搐），表明神经活动和兴奋性增加。事实上， 具有ALS相关基因突变的患者和啮齿动物模型已经确定了回路功能障碍， 特别是运动皮层兴奋过度是最早的病理之一。最近，两项研究表明， 运动皮层的上皮质脊髓运动神经元（CSMN）在下运动神经元中起重要作用， 表达人SOD 1突变的转基因小鼠的神经元死亡。因此，我们假设CSMN 过度兴奋可能驱动ALS发病机制。我们建议利用最近开发的增强子驱动的病毒 允许细胞特异性靶向的工具：1）执行尖端化学遗传学以调节神经元活性 以确定在症状前晚期抑制CSMN过度兴奋是否可以减轻ALS- 在SOD 1G 93 A小鼠中相关的行为和病理缺陷，和2）鉴定细胞特异性改变的分子 导致运动皮质过度兴奋的途径。这项研究对发展 针对ALS患者的这种早期临床异常的治疗。