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从阿尔茨海默病到帕金森病的神经退行性疾病的普遍特征。虽然疾病触发物的性质仅为家族性疾病所知，但此类触发物通常在整个CNS中广泛表达。这就提出了神经学中的一个基本问题：为什么特定的神经元亚群会对一种普遍表达的蛋白质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，其特征在于运动池的差异性丧失，运动池是解剖学上离散的运动神经元组，具有明确的功能-外周单个肌肉的收缩。例如，肋间肌的严重功能障碍与横膈膜的功能保留相结合产生了SMA的特征性的“钟形”胸部。此外，所有SMA患者均存在运动神经元存活（SMN）基因的纯合性功能丧失。因此，SMN缺失的小鼠模型代表了所有患者的疾病。研究SMA中的选择性运动池脆弱性可能会揭示可应用于其他疾病的选择性神经变性的原则。该项目旨在通过识别脆弱和抵抗运动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个 SMA中不同影响的运动池。这些运动池具有不同的生理机能、突触前连接和沿神经轴沿着的广泛解剖分布。因此，我假设差异表达的基因和途径是有助于抗病性的有希望的候选者。我将在SMN <$7 SMA小鼠模型中操纵这些候选基因，并评估病理学的改善，如细胞丢失或神经肌肉去神经支配。成功的候选基因代表了翻译成人类SMA和其他共享共同途径的神经退行性疾病的有希望的靶点。未来的研究重点是神经保护的潜在机制，可能会提供更广泛的神经退行性变的原理。

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.