Mechanisms underlying selective motor pool vulnerability in mouse and human SMA

描述(由申请人提供)：选择性丢失特定神经元亚群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。虽然疾病触发因素的性质仅在家族性疾病中已知，但这种触发因素通常在整个中枢神经系统中广泛表达。这提出了神经学中的一个基本问题：为什么神经元的特定亚群会因无处不在的表达蛋白质的功能障碍而退化？近端脊髓性肌萎缩症(SMA)为解决这些问题提供了一个独特的机会。肌萎缩侧索硬化症是一种致命的神经肌肉疾病，其特征是运动池的差异性丢失，即解剖上离散的运动神经元群，具有明确的功能--周围单一肌肉的收缩。例如，严重的肋间肌肉功能损害与隔膜功能保留相结合，会产生SMA的“钟形”胸部。此外，所有SMA患者都存在存活运动神经元(SMN)基因的纯合子功能丧失。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的选择性运动池脆弱性可能揭示选择性神经退行性变的原理，该原理可应用于其他疾病。该项目旨在通过识别脆弱运动池和抵抗运动池之间的内在分子差异来确定候选的治疗靶点。具体地说，我将分离RNA并对12个 SMA中受不同影响的机动池。这些运动池具有不同的生理、突触前连接和沿神经轴的广泛解剖分布。因此，我假设差异表达的基因和途径是有希望的有助于抗病的候选基因。我将在SMN？7小鼠SMA模型中操作这些候选基因，并评估病理上的改善，如细胞丢失或神经肌肉失神经。成功的候选基因代表着有希望转化为人类SMA和其他共享共同途径的神经退行性疾病的目标。未来专注于神经保护潜在机制的研究可能会对神经退行性变的原理提供更广泛的见解。

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.