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

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 ubiquitin-like modifier activating enzyme 1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signaling. 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.

Molecular Crosstalk Between Non-SMN-Related and SMN-Related Spinal Muscular Atrophy

“…13 In a separate study, lamin A/C overexpression increased nuclear levels of β-catenin and activated the Wnt signalling pathway to promote osteoblast differentiation. 14 Our recent study 3 further expanded on the link between lamin A/C and β-catenin by demonstrating that they interact in mouse heart extracts under normal physiological conditions. UBA1, on the other hand, controls the stability of β-catenin through the canonical ubiquitin-proteasome pathway, and deficiency in UBA1 protein levels leads to β-catenin accumulation and neuromuscular pathology in SMN-dependent SMA.…”

“…A minority (ie, <5%) of SMA cases involve genes other than SMN1 , and to date, at least 30 different genes have been attributed to cases of non-SMN-related SMA (reviewed by Farrar and Kiernan 2 ). Intriguingly, experimental evidence has emerged from our recent work 3 and the work of others that proteins produced by several non-SMN-related SMA genes, including LMNA , 3 UBE1 , 4,5 GARS , 6 and SETX , 7 are implicated in SMN-related SMA pathways.…”

“…Mutations in LMNA , the lamin A/C encoding gene, cause a range of neuromuscular conditions with prominent cardiac involvement, including an adult form of SMA, 8,9 and our recent study also proposes a role for lamin A/C in SMN-related SMA pathways. 3 Frequent reports of cardiac abnormalities in SMN-related SMA patients and mouse models of SMN-dependent SMA 10 prompted us to study the underlying molecular pathways using quantitative proteomics analysis. A key finding from this study was the identification of increased lamin A/C levels as a robust molecular phenotype in the heart of SMN-related SMA mice.…”

“…10 Lamin A/C dysregulation was also apparent in fibroblast cells from individuals with severe SMN-dependent SMA and in other tissues from SMN-dependent SMA mice, but with differing directions of expression change depending on the tissues examined. 3…”

Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy

“…Cardiac abnormalities 33 , 34 , pancreatic defects 35 , 36 , and liver deficits 37 , 38 have been reported in patients with SMA and in the murine model of SMA. Small-molecule compounds delivered systemically have the potential to increase the expression of SMN proteins, which are expressed ubiquitously in humans.…”