PCDHA9 as a candidate gene for amyotrophic lateral sclerosis

• Published in: Nature communications Vol. 15; no. 1; p. 2189
• Main Authors: Zhong, Jie, Wang, Chaodong, Zhang, Dan, Yao, Xiaoli, Zhao, Quanzhen, Huang, Xusheng, Lin, Feng, Xue, Chun, Wang, Yaqing, He, Ruojie, Li, Xu-Ying, Li, Qibin, Wang, Mingbang, Zhao, Shaoli, Afridi, Shabbir Khan, Zhou, Wenhao, Wang, Zhanjun, Xu, Yanming, Xu, Zhiheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/51; 14/19; 14/28; 14/32; 38/23; 38/91; 631/378/1689/1285; 631/378/2583; 631/80/82; 82/51; Abnormalities; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Animals; Atrophy; Axonal transport; Cell adhesion; Gene deletion; Genetic factors; Humanities and Social Sciences; Humans; Ion transport; Lethality; Mice; Mice, Transgenic; Motor neurons; Motor Neurons - metabolism; multidisciplinary; Mutants; Mutation; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurons; Paralysis; Pathogenesis; Pathology; Phenotypes; Point mutation; Science; Science (multidisciplinary); Spinal cord; Spinal Cord - metabolism; Structure-function relationships
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46333-5

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis. Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.