SEPN1-related myopathy depends on the ER oxidase ERO1 alpha and is responsive to the chemical chaperone TUDCA
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB64682 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11780100.fastq.gz | Fastqsanger.gz | |||
| ERR11780101.fastq.gz | Fastqsanger.gz | |||
| ERR11780102.fastq.gz | Fastqsanger.gz | |||
| ERR11780103.fastq.gz | Fastqsanger.gz | |||
| ERR11780104.fastq.gz | Fastqsanger.gz |
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Project description:SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA
2024-05-24 | PXD047157 | Pride
Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.
2024-02-14 | E-MTAB-12460 | biostudies-arrayexpress
Project description:As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.
2019-01-07 | MTBLS750 | MetaboLights
Project description:Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.
| S-EPMC10982971 | biostudies-literature
Project description:Background and Aims: In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC). Methods: Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes. Results: Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001). Conclusions: Six weeks of oral TUDCA promoted mucosal healing, lessened ER stress, and reduced UC clinical disease activity. TUDCA was safe and well-tolerated in patients with active UC. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted. ClinicalTrials.gov (NCT04114292).
2025-05-30 | GSE266963 | GEO
Project description:Cells respond to endoplasmic reticulum (ER) stress through activation of signaling pathways such as the Unfolded Protein Response (UPR) which improve the ER folding environment capacity upon changes in misfolded protein burden. Small molecules termed chemical chaperones can attenuate the UPR under stress conditions and improve folding and trafficking of specific mutant proteins. One such compound is the bile acid tauroursodeoxycholic acid (TUDCA). Despite promising results in multiple models of protein folding diseases, TUDCA’s mechanism of action remains unclear. To better define how TUDCA attenuate ER stress, we leveraged the genetically tractable budding yeast, S. cerevisiae. Consistent with properties described for TUDCA, we found it significantly improves growth of yeast subjected to ER stress caused by the N-glycosylation inhibitor tunicamycin (Tm) independently of activity of the UPR. In addition to other data, transcriptomics of strains treated with TUDCA link its ability to resuce Tm-induced stress with cell wall remodeling.
2024-11-13 | GSE186390 | GEO
Project description:The hypothesis tested in the present study was that ameliorating ER stress by TUDCA could reduce the cardiac remodeling in TAC mice. Results provide important information of the genes that were up- or down-regulated in Veh-TAC operated animals in comparison to Sham, TUDCA -Sham and TUDCA-TAC mice.
2017-04-12 | GSE89539 | GEO
Project description:Cholesterol efflux capacity dysfunction in macrophages is thought to be important in atherosclerosis. However, the molecular mechanism underlying this dysfunction remains unclear. Our previous analysis found that the increase of endoplasmic reticulum stress in macrophages during atherosclerotic plaque formation. Here we extended our analysis to ApoE-/- mice fed a high fat diet, some of which were treated with tauroursodeoxycholic acid (TUDCA) and collected the arteries of mice among these three groups (NFD, HFD and HFD+TUDCA) to perform the Bulk-RNA sequencing. There was significantly high expression of matrix metalloproteinase family (MMP9, MMP25, MMP8, MMP12, MMP13 and MMP3), CD68, inflammasome (IL1b, IL18bp, ifi44, ifi204 and Nlrp3), ER stress (Hspa5) and cholesterol transporters (ABCA1 and ABCG1) in the HFD group compared with the NFD group, however, TUDCA rescued the high expression of the above DEGs to different degrees. As shown by the expression levels of ifi204, Nlrp3, Il1b, and Il18, inflammasome activation was evident in the arteries of the HFD group compared to the NFD group. The ER stress inhibitor TUDCA not only decreased expression of the ER stress-related gene Hspa5 but also down-regulated inflammasome activation (as seen with the expression levels of ifi204, ifi44, NLRP3 and IL1b) in the artery of TUDCA treated mice compared with mice without drugs.
2024-03-05 | GSE260610 | GEO
Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group. Affymetrix 100K SNP arrays were used according to the manufacturers instructions with two pools of 19 and 20 statin myopathy patients and two pools of 20 statin-tolerant controls.
2010-07-09 | E-GEOD-17574 | biostudies-arrayexpress
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