Biology subjects

Vrettou, S.

Publications and source records attributed to Vrettou, S..

3 recordsLinked to original sources

bioRxiv2026

System-Wide Proteomic Remodeling in Spinal Muscular Atrophy Reveals Tissue-Specific Responses and Partial Rescue by SMN Restoration

Spinal muscular atrophy (SMA), traditionally defined as a neuromuscular disorder characterized by degeneration of lower motor neurons, is increasingly recognized as a multi-organ disease. SMA is caused by deficiency of the survival motor neuron (SMN) protein below a critical threshold required for cellular homeostasis. While motor neurons are particularly vulnerable, the ubiquitous expression and fundamental functions of SMN result in widespread perturbations across multiple tissues. Here, we generated a label-free quantitative proteomics atlas of spinal cord, heart, and gastrocnemius muscle from wild-type, heterozygous, and SMA mice at the symptomatic stage, including cohorts treated, at postnatal day 1 (P1), with a systemic suboptimal dose of SMN antisense oligonucleotides (SMN-ASOs), resulting in partial SMN restoration. SMN deficiency induced pronounced, tissue-specific proteome remodeling, with peripheral tissues exhibiting broader molecular alterations than spinal cord. Cross-tissue analyses revealed limited overlap, although heart and muscle showed partial convergence in metabolic and mitochondrial-associated pathways. SMN-ASO treatment partially repositioned these proteomes toward control states; however, restoration was incomplete and strongly tissue-dependent, with persistent dysregulation of mitochondrial and metabolic pathways. These findings demonstrate that SMN deficiency drives systemic yet heterogeneous proteome remodeling and that partial SMN restoration does not fully reverse established molecular alterations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/715402v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@114d73borg.highwire.dtl.DTLVardef@13e8c13org.highwire.dtl.DTLVardef@15e4ba0org.highwire.dtl.DTLVardef@1b70fb8_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts

Spinal muscular atrophy (SMA) is caused by loss of SMN protein and is increasingly recognized as a multisystem disorder involving molecular pathology beyond motor neurons. Recently, we identified NRF2-KEAP1 signaling as dysregulated in SMA mice. Because NRF2 coordinates transcriptional programs that maintain cellular redox homeostasis and adaptive stress responses, we investigated whether NRF2 signaling is similarly altered in SMA type I patient-derived fibroblasts and whether it can be pharmacologically engaged. Compared with control fibroblasts, SMA fibroblasts displayed reduced basal expression of NRF2 target proteins, including NQO1 and xCT (SLC7A11), along with decreased levels of PGC1. Omaveloxolone (OMAV), a pharmacological NRF2 activator approved for the treatment of Friedreichs ataxia, increased cell viability and upregulated NRF2 target proteins in both control and SMA fibroblasts. Notably, OMAV produced a modest increase in SMN protein abundance and PGC1 levels selectively in SMA cells. Together, these findings support diminished NRF2 pathway output as a feature of SMA fibroblasts and demonstrate that OMAV induces NRF2 target proteins in this human SMA cellular model, consistent with enhanced cytoprotective signaling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/712434v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@19b82b0org.highwire.dtl.DTLVardef@a11691org.highwire.dtl.DTLVardef@1d089e9org.highwire.dtl.DTLVardef@e48ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

SMN deficiency disrupts hepatic mitochondrial iron homeostasis and NRF2-dependent redox control in spinal muscular atrophy

Spinal muscular atrophy (SMA), classically defined as a motor neuron disorder caused by deficiency of the survival motor neuron (SMN) protein, is increasingly recognized as a multi-system disease. Among peripheral organs, the liver, essential for metabolic regulation and xenobiotic processing, remains underexplored despite growing evidence of dysfunction. Defining hepatic contributions may be critical for understanding systemic disease progression and optimizing therapeutic strategies. Here, we performed integrative profiling of liver pathology in SMA by combining unbiased proteomics from wild-type (WT), heterozygous (HET), and SMA mice at the late symptomatic stage (postnatal day 10; P10) with targeted analyses of mitochondrial function, iron metabolism, and redox homeostasis. To resolve temporal dynamics, key pathways were examined at early symptomatic disease (P5), and the reversibility of identified defects was evaluated following SMN-restoring antisense oligonucleotide (ASO) therapy. We uncover early (P5) activation of the heme biosynthetic pathway, marked by increased ferrochelatase (FECH), preceding overt metabolic disruption. By P10, SMA liver shows a coordinated loss of mitochondrial Complex II integrity, pathological mitochondrial iron accumulation, disruption of the NRF2-KEAP1 antioxidant axis, and heightened susceptibility to ferroptotic redox stress. ASO treatment robustly restored mitochondrial and redox phenotypes, yet FECH remained elevated, indicating sustained heme pathway activation despite SMN rescue. HET mice displayed mild redox abnormalities, revealing a dosage-sensitive hepatic phenotype. Collectively, these findings delineate a mitochondrial-iron-redox axis uniquely vulnerable in SMA liver, identify ferroptotic sensitivity as an early and therapeutically responsive feature, and highlight persistent heme biosynthesis activation as a target to complement SMN-directed therapies.

cell biology↗