Neurology Clinic, Clinical Center of Serbia, 11000 Belgrade, Serbia.
Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
Int J Mol Sci. 2021 Sep 11;22(18):9832. doi: 10.3390/ijms22189832.
Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.
肌萎缩侧索硬化症（ALS），一种神经退行性运动神经元疾病，其特征是多系统疾病，遗传因素有重要贡献。ALS 的病因发病机制尚未完全阐明，但目前占主导地位的理论与 RNA 加工以及蛋白质聚集和错误折叠、氧化应激、谷氨酸兴奋性毒性、炎症和表观遗传失调有关。此外，由于线粒体在细胞内稳态维持中起着主导作用，越来越多的证据表明线粒体功能障碍是疾病发生和进展的重要因素。本文综述的目的是总结与 ALS 发病机制中的遗传因素相关的最相关发现，这些发现与线粒体参与的不同机制有关（呼吸链、OXPHOS 控制、钙缓冲、轴突运输、炎症、线粒体自噬等）。我们强调了拓宽视野的重要性，以便更好地理解 ALS 和一般神经退行性变中重叠的病理生理途径。最后，简要讨论了当前和潜在的新型治疗方法，特别是针对线粒体功能障碍的基因特异性治疗方法。
