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

神经退行性疾病的特点是特定神经细胞类型的选择性死亡。虽然对理解神经变性和设计有效的治疗方法至关重要，但对神经变性差异敏感性的分子性质仍然不清楚。肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是进行性肌肉失神经支配和运动神经元的丧失导致瘫痪。然而，并不是所有的运动神经元都受到同样的影响。大多数脊髓运动神经元（SpMNs）在ALS进展过程中退行性变

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.