Functional identification of protocadherin alpha 9 (PCDHA9) as a candidate causative gene for amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic contributors to ALS, we analyzed exome sequences in a large cohort of Chinese ALS patients. We found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients but not in publicly available genomic databases. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice developed progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. Importantly, TDP-43 pathology was observed in the ventral spinal motor neurons of aged point mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in the aged spinal cord. Furthermore, we uncovered a novel PCDHA9-interacting protein, Na + /K + ATPase-α1, and its dramatically reduced expression in mutant motor neurons. Accordingly, single nucleus multi-omics analysis revealed disturbed networks or signaling involved in cell/cell-cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a new candidate ALS gene and provide insights into its pathogenesis.