TY - JOUR
T1 - An impaired splicing program underlies differentiation defects in hSOD1G93A neural progenitor cells
AU - Verdile, Veronica
AU - Riccioni, Veronica
AU - Guerra, Marika
AU - Ferrante, Gabriele
AU - Sette, Claudio
AU - Valle, Cristiana
AU - Ferri, Alberto
AU - Paronetto, Maria Paola
PY - 2023
Y1 - 2023
N2 - 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(G93A) mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel, hSOD1(G93A) 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(G93A) NPCs, thus impacting the differentiation program. Our data indicate that hSOD1(G93A) 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.
AB - 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(G93A) mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel, hSOD1(G93A) 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(G93A) NPCs, thus impacting the differentiation program. Our data indicate that hSOD1(G93A) 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.
KW - ALS
KW - Alternative splicing
KW - Neural progenitor cells
KW - ALS
KW - Alternative splicing
KW - Neural progenitor cells
UR - http://hdl.handle.net/10807/272882
U2 - 10.1007/s00018-023-04893-7
DO - 10.1007/s00018-023-04893-7
M3 - Article
SN - 1420-9071
VL - 80
SP - 236
EP - 248
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
ER -