PCDHA9 as a candidate gene for amyotrophic lateral sclerosis

Jie Zhong, Chaodong Wang (), Dan Zhang, Xiaoli Yao, Quanzhen Zhao, Xusheng Huang, Feng Lin, Chun Xue, Yaqing Wang, Ruojie He, Xu-Ying Li, Qibin Li, Mingbang Wang, Shaoli Zhao, Shabbir Khan Afridi, Wenhao Zhou, Zhanjun Wang, Yanming Xu () and Zhiheng Xu ()
Additional contact information
Jie Zhong: Chinese Academy of Sciences
Chaodong Wang: Capital Medical University, National Clinical Research Center for Geriatric Disease
Dan Zhang: Chinese Academy of Sciences
Xiaoli Yao: Sun Yat-sen University
Quanzhen Zhao: Sichuan University
Xusheng Huang: The First Medical Center, Chinese PLA General Hospital
Feng Lin: Fujian Medical University Union Hospital
Chun Xue: Chinese Academy of Sciences
Yaqing Wang: Chinese Academy of Sciences
Ruojie He: Sun Yat-sen University
Xu-Ying Li: Capital Medical University, National Clinical Research Center for Geriatric Disease
Qibin Li: Shenzhen Clabee Biotechnology Incorporation
Mingbang Wang: National Center for Children’s Health
Shaoli Zhao: Chinese Academy of Sciences
Shabbir Khan Afridi: Chinese Academy of Sciences
Wenhao Zhou: National Center for Children’s Health
Zhanjun Wang: Capital Medical University, National Clinical Research Center for Geriatric Disease
Yanming Xu: Sichuan University
Zhiheng Xu: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46333-5

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