1 Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.
2 Niedersachsen Network on Neuroinfectiology (N-RENNT), Hannover, Germany.
Neuroscientist. 2018 Feb;24(1):54-72. doi: 10.1177/1073858417705059. Epub 2017 May 1.
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases with overlapping clinical phenotypes based on impaired motoneuron function. However, the pathomechanisms of both diseases are largely unknown, and it is still unclear whether they converge on the molecular level. SMA is a monogenic disease caused by low levels of functional Survival of Motoneuron (SMN) protein, whereas ALS involves multiple genes as well as environmental factors. Recent evidence argues for involvement of actin regulation as a causative and dysregulated process in both diseases. ALS-causing mutations in the actin-binding protein profilin-1 as well as the ability of the SMN protein to directly bind to profilins argue in favor of a common molecular mechanism involving the actin cytoskeleton. Profilins are major regulat ors of actin-dynamics being involved in multiple neuronal motility and transport processes as well as modulation of synaptic functions that are impaired in models of both motoneuron diseases. In this article, we review the current literature in SMA and ALS research with a focus on the actin cytoskeleton. We propose a common molecular mechanism that explains the degeneration of motoneurons for SMA and some cases of ALS.
肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）是神经退行性疾病，基于运动神经元功能受损，具有重叠的临床表型。然而，这两种疾病的发病机制在很大程度上尚不清楚，它们是否在分子水平上趋于一致也不清楚。SMA 是一种由运动神经元生存（SMN）蛋白功能低下引起的单基因疾病，而 ALS 则涉及多个基因以及环境因素。最近的证据表明，肌动蛋白调节的参与是这两种疾病的一个致病和失调过程。肌动蛋白结合蛋白细丝蛋白-1中的 ALS 致病突变，以及 SMN 蛋白直接与细丝蛋白结合的能力，都支持涉及肌动蛋白细胞骨架的共同分子机制。细丝蛋白是肌动蛋白动力学的主要调节剂，参与多种神经元运动和运输过程，以及调节突触功能，在运动神经元疾病的模型中，这些功能都受到损害。在本文中，我们综述了 SMA 和 ALS 研究的最新文献，重点关注肌动蛋白细胞骨架。我们提出了一个共同的分子机制，解释了 SMA 和一些 ALS 病例中运动神经元的退化。
