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 β-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.
Original language | English |
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Pages (from-to) | 3515–3527 |
Number of pages | 13 |
Journal | Human Molecular Genetics |
Volume | 28 |
Issue number | 21 |
Early online date | 9 Aug 2019 |
DOIs | |
Publication status | Published - 1 Nov 2019 |
Bibliographical note
The authors would like to thank Prof Colin L Stewart, Institute of Medical Biology,Singapore, for kindly providing wild type and LMNA knockout mouse embryonic fibroblasts, and Prof Glenn E Morris for helpful discussions about lamin A and for providing access to laboratory equipment. This research was supported by funding from the Newlife Charity [SG/15-16/11] (HF) and Keele University ACORN funding (HF & DS); British Heart Foundation [PG/16/68/31991] (IH); UK SMA Research Consortium (SMA Trust) (THG) and the Euan MacDonald Centre for Motor Neurone Disease Research (HKS and THG); and Wellcome Trust [094476/Z/10/Z] (SLS).
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Simon Parson
- School of Medicine, Medical Sciences & Nutrition, Medical Education - Regius Chair of Anatomy
- The Suttie Centre - Anatomy
Person: Academic