Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 6, 00135, Rome, Italy.
Laboratory of Molecular and Cellular Neurobiology and of Neurochemistry, Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
Cell Mol Life Sci. 2023 Jul 31;80(8):236. doi: 10.1007/s00018-023-04893-7.
Amyotrophic lateral sclerosis (ALS) is an adult devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), resulting in progressive paralysis and death. Genetic animal models of ALS have highlighted dysregulation of synaptic structure and function as a pathogenic feature of ALS-onset and progression. Alternative pre-mRNA splicing (AS), which allows expansion of the coding power of genomes by generating multiple transcript isoforms from each gene, is widely associated with synapse formation and functional specification. Deciphering the link between aberrant splicing regulation and pathogenic features of ALS could pave the ground for novel therapeutic opportunities. Herein, we found that neural progenitor cells (NPCs) derived from the hSOD1 mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel, hSOD1 NPCs showed impaired splicing patterns in synaptic genes, which could contribute to the observed phenotype. Remarkably, master splicing regulators of the switch from stemness to neural differentiation are de-regulated in hSOD1 NPCs, thus impacting the differentiation program. Our data indicate that hSOD1 mutation impacts on neurogenesis by increasing the NPC pool in the developing mouse cortex and affecting their intrinsic properties, through the establishment of a specific splicing program.
肌萎缩侧索硬化症（ALS）是一种成人毁灭性的神经退行性疾病，其特征是上下运动神经元（MNs）的丧失，导致进行性瘫痪和死亡。ALS 的遗传动物模型强调了突触结构和功能的失调是 ALS 发病和进展的致病特征。选择性剪接（AS）可以通过从每个基因产生多个转录本异构体来扩展基因组的编码能力，它与突触形成和功能特化广泛相关。阐明异常剪接调控与 ALS 致病特征之间的联系，可以为新的治疗机会铺平道路。在这里，我们发现来自 ALS 的 hSOD1 小鼠模型的神经祖细胞（NPCs）显示出增殖增加和倾向于分化为神经元的能力。平行地，hSOD1 NPCs 显示出突触基因中的剪接模式受损，这可能导致观察到的表型。值得注意的是，hSOD1 NPCs 中调节干性向神经分化转变的主要剪接调控因子失调，从而影响分化程序。我们的数据表明，hSOD1 突变通过增加发育中小鼠皮层中的 NPC 池并通过建立特定的剪接程序来影响其内在特性，从而影响神经发生。
