An impaired splicing program underlies differentiation defects in hSOD1 G93A neural progenitor cells

• Published in: Cellular and molecular life sciences : CMLS 2023-07, Vol.80 (8), p.236
• Main Authors: Verdile, Veronica, Riccioni, Veronica, Guerra, Marika, Ferrante, Gabriele, Sette, Claudio, Valle, Cristiana, Ferri, Alberto, Paronetto, Maria Paola
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Cell Differentiation - genetics; Cell Proliferation - genetics; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Motor Neurons - metabolism; Motor Neurons - pathology; Mutation; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis - genetics; RNA Splicing - genetics; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 1420-9071

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.