A comparative inter-neuronal and inter-species platform to understand neuronal differential sensitivity to neurodegeneration

神经退行性疾病的特征在于特定神经元细胞类型的选择性死亡。尽管对理解神经变性和设计有效的治疗方法至关重要，但对神经变性的不同敏感性的分子本质仍然不清楚。肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种以进行性肌肉失神经支配和运动神经元丧失为特征的致死性神经退行性疾病，导致瘫痪。然而，并不是所有的运动神经元都受到同样的影响。虽然大多数脊髓运动神经元（SpMN）在ALS进展过程中退化， 在一些实施例中，头侧颅运动神经元（CrMN：眼运动神经元、眼运动神经元和外展运动神经元）的一个子集通常被保留，允许患者保持眼球运动直到疾病的晚期。因此，ALS患者利用眼动跟踪设备进行通信，直到疾病晚期。ALS抗性似乎是一个保守的特征，因为在表达具有G93A突变的人超氧化物歧化酶1（hSOD 1）的ALS小鼠模型中，眼神经元和trophilar运动神经元也比SpMN对神经变性更具抗性。我们已经建立了一个有效的胚胎干细胞分化平台，产生ALS敏感和耐运动神经元。我们已经用胚胎来源的运动神经元验证了这种体外系统的预测能力，并确定了维持健康的运动神经元的能力。 蛋白质组作为一种可能的运动神经元抵抗ALS的内在机制。本申请的目标是产生预测性人类干细胞分化系统，其将补充模型生物体以理解有助于运动神经元分化ALS敏感性的内在神经元机制，从而加深我们对ALS病理学的理解并激发有效的治疗。

Neurodegenerative diseases are characterized by the selective death of specific neuronal cell types. Although fundamental to understanding neurodegeneration and designing effective therapies, the molecular nature of differential sensitivity to neurodegeneration remains obscure. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle denervation and loss of motor neurons leading to paralysis. However, not all motor neurons are affected equally. While most spinal motor neurons (SpMNs) degenerate during ALS progression, a subset of rostral cranial motor neurons (CrMNs: oculomotor, trochlear and abducens motor neurons) are typically spared, allowing patients to retain eye movement until late stages of the disease. Thus, ALS patients utilize eye tracking devices to communicate until late disease stages. The ALS resistance seems to be a conserved feature since oculomotor and trochlear motor neurons are also more resistant than SpMNs to neurodegeneration in the ALS mouse model expressing human superoxide dismutase 1 (hSOD1) with G93A mutation. We have established an efficient embryonic stem cell differentiation platform that produces ALS-sensitive and -resistant motor neurons. We have validated the predictive power of this in vitro system with embryonically-derived motor neurons and have identified the ability to maintain a healthy proteome as a possible motor neuron intrinsic mechanism to resist ALS. The goal of this application is to generate a predictive human stem cell differentiation system that will complement model organisms to understand the intrinsic neuronal mechanisms that contribute to motor neuron differential ALS sensitivity to deepen our understanding of ALS pathology and inspire effective therapies.