PCDHA9 as a Candidate Gene for Amyotrophic Lateral Sclerosis
    作者: 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, Zhiheng Xu
    刊物名称: Nature Communications
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    摘要:
    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 Pcdhalpha9 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-alpha1 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.