AI Article Synopsis
- ALS is a severe neurodegenerative disease, and researchers found a specific genetic mutation (p.L700P) in the PCDHA9 gene among Chinese ALS patients.
- They created mutant mice with this gene alteration, which showed symptoms like motor loss, muscle wasting, and early death, similar to human ALS.
- The study also revealed that the mutation disrupts key cellular signaling pathways related to neuronal health and may identify PCDHA9 as a new potential gene linked to ALS.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928119 | PMC |
| http://dx.doi.org/10.1038/s41467-024-46333-5 | DOI Listing |
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