Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
journal contributionposted on 2020-08-27, 15:36 authored by Raphaelle Luisier, Giulia E Tyzack, Claire E Hall, Jamie S Mitchell, Helen Devine, Doaa M Taha, Bilal Malik, Ione Meyer, Linda Greensmith, Jia Newcombe, Jernej Ule, Nicholas M Luscombe, Rickie Patani
Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.
AgedAmyotrophic Lateral SclerosisAnimalsCell DifferentiationDisease Models, AnimalExonsFibroblastsHumansInduced Pluripotent Stem CellsIntronsMiceMice, Inbred C57BLMice, TransgenicMiddle AgedMotor NeuronsPTB-Associated Splicing FactorPrimary Cell CultureRNA SplicingRNA-Binding Protein FUSSequence Analysis, RNASpinal CordSuperoxide Dismutase-1Valosin Containing ProteinLuscombe FC001110Ule - secPatani - sec