Mechanisms underlying selective motor pool vulnerability in mouse and human SMA

描述（由申请人提供）：特定神经元亚群的选择性丧失是神经退行性疾病的普遍特征，从阿尔茨海默病到帕金森病。虽然疾病触发的性质仅为家族性疾病所知，但这种触发通常在整个中枢神经系统中广泛表达。这就提出了神经学的一个基本问题：为什么特定的神经元亚群会对一种无处不在的表达蛋白的功能障碍做出反应而退化？近端脊髓性肌萎缩症（SMA）提供了一个独特的机会来解决这些问题。SMA是一种致命的神经肌肉疾病，其特征是运动池的差异丧失，运动池是解剖学上离散的运动神经元群，具有明确的功能-周围单个肌肉的收缩。例如，严重的肋间肌功能损伤与横膈膜功能保留相结合会产生“钟形”胸部，这是SMA的典型症状。此外，所有SMA患者均存在存活运动神经元（SMN）基因的纯合性功能缺失。因此，SMN缺失的小鼠模型在所有患者中都具有代表性。研究SMA的选择性运动池易损性可能揭示选择性神经变性的原理，可应用于其他疾病。该项目旨在通过识别易感和耐药汽车池之间的内在分子差异来确定候选治疗靶点。具体来说，我将分离RNA并对12进行转录分析

DESCRIPTION (provided by applicant): Selective loss of specific neuronal subsets is a universal feature of neurodegenerative diseases ranging, from Alzheimer's disease to Parkinson's disease. Although the nature of the disease trigger is only known for familial forms of disease, such triggers are in general expressed widely throughout the CNS. This raises a fundamental question in neurology: why do specific subsets of neurons degenerate in response to dysfunction of a ubiquitously expressed protein? Proximal spinal muscular atrophy (SMA) provides a unique opportunity to address these questions. SMA is a fatal neuromuscular disease characterized by differential loss of motor pools, anatomically discrete groups of motor neurons with a well-defined function - contraction of a single muscle in the periphery. For example, severe functional impairment of intercostal muscles in combination with functional sparing of the diaphragm produces a "bell-shaped" chest that is pathognomonic of SMA. Moreover, all patients with SMA have homozygous loss of function of the survival motor neuron (SMN) gene. Mouse models with loss of SMN are therefore representative of the disease in all patients. Studying selective motor pool vulnerability in SMA may uncover principles of selective neurodegeneration that can be applied to other disorders. This project aims to identify candidate therapeutic targets by identifying intrinsic molecular differences between vulnerable and resistant motor pools. Specifically, I will isolate RNA and perform transcriptional profiling on 12 differentially affected motor pools in SMA. These motor pools have diverse physiology, presynaptic connectivity, and wide anatomic distribution along the neuraxis. Therefore, I hypothesize that differentially expressed genes and pathways are promising candidates for contributing to disease resistance. I will manipulate these candidate genes in the SMN¿7 mouse model of SMA and assess for improvements in pathology, such as cell loss or neuromuscular denervation. Successful candidate genes represent promising targets for translation into human SMA and other neurodegenerative disorders that share common pathways. Future studies that focus on underlying mechanisms of neuroprotection may provide insight into principles of neurodegeneration broadly.