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

Valentina Marchica; Luca Biasetti; Jodi Barnard; Shujing Li; Nikolas Nikolaou; Matthew P Frosch; Diane E Lucente; Mark Eldaief; Andrew King; Manolis Fanto; Claire Troakes; Corinne Houart; Bradley N Smith

doi:10.1093/brain/awae226

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

Brain. 2024 Jul 11:awae226. doi: 10.1093/brain/awae226. Online ahead of print.

Authors

Valentina Marchica^{1

2}, Luca Biasetti¹, Jodi Barnard¹, Shujing Li¹, Nikolas Nikolaou³, Matthew P Frosch^{4

5}, Diane E Lucente⁶, Mark Eldaief⁴, Andrew King^{1

7}, Manolis Fanto¹, Claire Troakes^{1

7}, Corinne Houart², Bradley N Smith^{1

2}

Affiliations

¹ Department of Basic and Clinical Neuroscience, Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 1 Camberwell, SE5 9NU London, UK.
² Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College London, London SE1 1UL, UK.
³ Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK.
⁴ Mass General Institute for Neurodegenerative Diseases, B114-2700, Charlestown, MA 02129, USA.
⁵ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ London Neurodegenerative Diseases Brain Bank, SGDP Centre, PO65, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.

PMID: 38989900
DOI: 10.1093/brain/awae226

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.

Keywords: amyotrophic lateral sclerosis; annexin A11; lamin B2; nuclear envelope.