PCDHA9 as a candidate gene for amyotrophic lateral sclerosis
© 2024. The Author(s)..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
---|---|
Enthalten in: |
Nature communications - 15(2024), 1 vom: 11. März, Seite 2189 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Zhong, Jie [VerfasserIn] |
---|
Links: |
---|
Themen: |
---|
Anmerkungen: |
Date Completed 13.03.2024 Date Revised 15.03.2024 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.1038/s41467-024-46333-5 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM369573358 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM369573358 | ||
003 | DE-627 | ||
005 | 20240315233552.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240312s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s41467-024-46333-5 |2 doi | |
028 | 5 | 2 | |a pubmed24n1330.xml |
035 | |a (DE-627)NLM369573358 | ||
035 | |a (NLM)38467605 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Zhong, Jie |e verfasserin |4 aut | |
245 | 1 | 0 | |a PCDHA9 as a candidate gene for amyotrophic lateral sclerosis |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 13.03.2024 | ||
500 | |a Date Revised 15.03.2024 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024. The Author(s). | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
700 | 1 | |a Wang, Chaodong |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Dan |e verfasserin |4 aut | |
700 | 1 | |a Yao, Xiaoli |e verfasserin |4 aut | |
700 | 1 | |a Zhao, Quanzhen |e verfasserin |4 aut | |
700 | 1 | |a Huang, Xusheng |e verfasserin |4 aut | |
700 | 1 | |a Lin, Feng |e verfasserin |4 aut | |
700 | 1 | |a Xue, Chun |e verfasserin |4 aut | |
700 | 1 | |a Wang, Yaqing |e verfasserin |4 aut | |
700 | 1 | |a He, Ruojie |e verfasserin |4 aut | |
700 | 1 | |a Li, Xu-Ying |e verfasserin |4 aut | |
700 | 1 | |a Li, Qibin |e verfasserin |4 aut | |
700 | 1 | |a Wang, Mingbang |e verfasserin |4 aut | |
700 | 1 | |a Zhao, Shaoli |e verfasserin |4 aut | |
700 | 1 | |a Afridi, Shabbir Khan |e verfasserin |4 aut | |
700 | 1 | |a Zhou, Wenhao |e verfasserin |4 aut | |
700 | 1 | |a Wang, Zhanjun |e verfasserin |4 aut | |
700 | 1 | |a Xu, Yanming |e verfasserin |4 aut | |
700 | 1 | |a Xu, Zhiheng |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 15(2024), 1 vom: 11. März, Seite 2189 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g day:11 |g month:03 |g pages:2189 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-024-46333-5 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 15 |j 2024 |e 1 |b 11 |c 03 |h 2189 |