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Brain. 2024 Jul 11:awae226. doi: 10.1093/brain/awae226. Online ahead of print.
ABSTRACT
Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.
PMID:38989900 | DOI:10.1093/brain/awae226
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Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue
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Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue
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Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue
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