Genomic and Functional studies identify RPSA as a risk gene for ALS and other neurological diseases

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron deterioration. Genetic factors play a significant role in all cases, with 15 genome-wide significant study (GWAS) risk loci identified to date. Follow-up of these loci is a powerful strategy for research translation, as drug targets supported by genetic evidence are more likely to succeed in clinical development. Here, we focus on the RPSA-MOBP locus on chromosome 3 (lead SNP, rs631312, OR = 1.08 95% CI: 1.06-1.10, p = 3.3 x 10-{superscript 1}{superscript 2}). We employ integrative in silico analyses to prioritise candidate genes, combining multiple omics-based approaches, including Functional Mapping and Annotation (FUMA), Polygenic Priority Scoring (PoPS), Transcriptome-Wide Association across/within tissues (TWAS), gene-based test (mBAT-combo), chromatin interaction mapping (H-MAGMA), and Summary data Mendelian Randomisation (SMR), with GWAS data (Ncases = 29,612, Ncontrols = 122,656). Both RPSA and MOBP were prioritised as candidate genes in multiple analyses. In-vivo expression analyses in ALS blood or iPSC-motor neurons were unremarkable for these genes but also other-relevant ALS genes. RPSA, highly conserved in zebrafish (92% homology), was selected for functional modelling, noting previously generated Mobp-ko mice show minimal phenotypic changes. CRISPR/Cas9-induced rpsa loss-of-function (LOF) in zebrafish triggers progressive and severe phenotypes mimicking pathology observed in SMN- and TDP43-deficient zebrafish, two key proteins/genes associated with diseases of the motor neurons. RPSA-deficient animals exhibit marked motor neuron axon pathology, progressive loss of motor function and rapid decline culminating with premature death at around 7 days- post-fertilisation. These phenotypes were notably similar to those observed in SMN and TDP-43 zebrafish models, together with prominent cardiovascular abnormalities. This study identifies RPSA as a critical gene for motor neuron health, with implications for ALS pathogenesis. The RPSA/MOBP locus is also associated with other neurodegenerative diseases including frontotemporal dementia/FTD, corticobasal degeneration/CBD and progressive supranuclear palsy/PSP, highlighting its potential as a therapeutic target for multiple conditions.