UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK.
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK.
Cells. 2024 May 7;13(10):792. doi: 10.3390/cells13100792.
The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.
在肌萎缩侧索硬化症（ALS）患者中，受影响的主要神经回路是皮质脊髓运动回路，它起源于大脑运动皮层中的上运动神经元（UMN），并向下延伸与脊髓中的下运动神经元（LMN）突触，最终支配骨骼肌。这些神经回路的紊乱以及随之而来的 UMN 和 LMN 的丧失，导致肌肉消耗和运动功能受损，是观察到的关键病理生理学现象。尽管经过了几十年的研究，我们仍然缺乏能够改变 ALS 疾病进程的治疗方法。在这篇综述中，我们记录了目前从患者研究、啮齿动物模型和人类干细胞模型中获得的研究结果，以了解皮质运动回路功能障碍的机制及其在 ALS 中的意义。我们总结了目前关于皮质 UMN 功能障碍和退化、LMN 兴奋性改变、神经肌肉接头退化以及胶质细胞在运动回路功能障碍中的非细胞自主作用的相关知识，这些都与 ALS 有关。我们进一步强调了人类干细胞技术在模拟复杂神经回路方面的进展，以及这些技术如何有助于未来的研究，从而更好地理解 ALS 中神经回路功能障碍的机制。
