Ludwig Institute and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
Department of Anesthesiology and Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.
Nat Neurosci. 2024 Jan;27(1):34-47. doi: 10.1038/s41593-023-01496-0. Epub 2023 Nov 23.
The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.
人类 STMN2 基因的 mRNA 转录本，编码 stathmin-2 蛋白（也称为 SCG10），其功能受到 TAR DNA 结合蛋白 43（TDP-43）功能丧失的显著影响。后者是几种神经退行性疾病的标志，包括肌萎缩侧索硬化症（ALS）。我们使用多种方法，包括瞬时反义寡核苷酸介导的抑制、衰老小鼠中持续 shRNA 诱导的耗竭以及种系缺失，表明 stathmin-2 在神经丝依赖性轴浆组织的建立和维持中具有重要作用，这对于维持有髓大直径轴突的直径和传导速度至关重要。成年小鼠中持续的 stathmin-2 缺失会导致 ALS 中发现的病理学，包括神经丝间隔减小、轴突直径塌陷导致外髓鞘层内撕裂、传导速度降低、进行性运动和感觉缺陷以及肌肉失神经支配。这些发现强调了恢复 stathmin-2 作为肌萎缩侧索硬化症和其他 TDP-43 依赖性神经退行性疾病有吸引力的治疗方法的重要性。
