PCDHA9 as a candidate gene for amyotrophic lateral sclerosis.

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

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.

Afiliación

Zhong J; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Wang C; University of Chinese Academy of Sciences, Beijing, 100101, China.
Zhang D; Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China. cdongwang@xwhosp.org.
Yao X; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Zhao Q; University of Chinese Academy of Sciences, Beijing, 100101, China.
Huang X; Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Lin F; Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Xue C; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Wang Y; Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
He R; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Li XY; University of Chinese Academy of Sciences, Beijing, 100101, China.
Li Q; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Wang M; University of Chinese Academy of Sciences, Beijing, 100101, China.
Zhao S; Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Afridi SK; Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China.
Zhou W; Shenzhen Clabee Biotechnology Incorporation, Shenzhen, 518057, China.
Wang Z; Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, 201102, China.
Xu Y; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Xu Z; University of Chinese Academy of Sciences, Beijing, 100101, China.

Nat Commun ; 15(1): 2189, 2024 Mar 11.

Article en En | MEDLINE | ID: mdl-38467605

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.

Asunto(s)

Esclerosis Amiotrófica Lateral; Enfermedades Neurodegenerativas; Humanos; Ratones; Animales; Anciano; Esclerosis Amiotrófica Lateral/metabolismo; Enfermedades Neurodegenerativas/metabolismo; Ratones Transgénicos; Neuronas Motoras/metabolismo; Médula Espinal/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas / Esclerosis Amiotrófica Lateral Límite: Aged / Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

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