Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy

Šoltić, Darija; Shorrock, Hannah K; Allardyce, Hazel; Wilson, Emma L; Holt, Ian; Synowsky, Silvia A; Shirran, Sally L; Parson, Simon H; Gillingwater, Thomas H; Fuller, Heidi

Abstract

Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice, and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in-vitro by knockdown of the E1 ubiquitination factor UBA1, a key downstream mediator of SMN-dependent disease pathways, converging on ß-catenin signalling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.

Citation

Šoltić, D., Shorrock, H. K., Allardyce, H., Wilson, E. L., Holt, I., Synowsky, S. A., …Fuller, H. (2019). Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy. Human Molecular Genetics, 3515-3527. https://doi.org/10.1093/hmg/ddz195

• Acceptance Date: Jul 25, 2019
• Publication Date: Nov 1, 2019
• Journal: Human Molecular Genetics
• Print ISSN: 0964-6906
• Publisher: Oxford University Press
• Pages: 3515-3527
• DOI: https://doi.org/10.1093/hmg/ddz195
• Keywords: spinal muscular atrophy, SMA, Lamin A/C, Heart, Proteomics
• Publisher URL: http://doi.org/10.1093/hmg/ddz195