Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue

TY - JOUR

T1 - Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue

AU - Marchica, Valentina

AU - Biasetti, Luca

AU - Nikolaou, Nikolas

AU - Barnard, Jodi

AU - King, Andrew

AU - Fanto, Manolis

AU - Lucente, Diane

AU - Eldaief, Mark

AU - Frosch, Matthew

AU - Troakes, Claire

AU - Houart, Corinne

AU - Smith, Bradley

PY - 2024/7/11

Y1 - 2024/7/11

N2 - 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 helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function 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 wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia 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.

AB - 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 helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function 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 wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia 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.

U2 - 10.1093/brain/awae226

DO - 10.1093/brain/awae226

M3 - Article

SN - 0006-8950

VL - 148

SP - 276

EP - 290

JO - Brain

JF - Brain

IS - 1

ER -