Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
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PROVIDER: PRJNA1057744 | ENA |
REPOSITORIES: ENA
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Project description:Genetics of Charcot-Marie-Tooth Disease
| PRJNA382008 | ENA
Project description:Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves protein misfolding and retention in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1/XBP1 pathways. Previous studies have reported that targeting PERK pathway can mitigate the neuropathy in CMT1B mice. To unravel the role of the XBP1 pathway in normal myelination and in CMT1B, we generated mouse models of in which XBP1 is deleted specifically in Schwann cells. We observed that whereas XBP1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury, the absence of XBP1 dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1 exerts its adaptive function in large part via the induction of genes involved in misfolded protein degradation. Accordingly, the exacerbation of the neuropathy was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling, suggesting that the activation of XBP1 plays a critical role in limiting mutant proteins toxicity, which cannot be compensated by other stress responses. Schwann cell specific overexpression of spliced XBP1 partially re-established Schwann cell proteostasis and attenuated CMT1B severity in vivo in both the S63del and R98C mouse models. In addition, the pharmacologic selective activation of XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants.
2024-01-15 | GSE252089 | GEO
Project description:Genomic Studies in Charcot-Marie-Tooth Disease
| PRJNA1006093 | ENA
Project description:Genomic Studies in Charcot-Marie-Tooth Disease
| PRJNA1006094 | ENA
Project description:Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic target for CMT.
2019-10-01 | GSE125311 | GEO
Project description:Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
| S-EPMC10862880 | biostudies-literature
Project description:Hyper-activation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2
| PRJNA377238 | ENA
Project description:Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy with impact on the entire nervous system. To date, no curative treatment is available. In the paper we propose a novel therapeutic strategy tailored to correct the root genetic defect of CMT2A. In our approach, while mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing a cDNA encoding a functional MFN2, modified to be resistant to RNAi. This strategy allows proper MFN2 molecular correction in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs via adenoassociated virus 9 (AAV9) in newborn mice. To identify the therapeutic molecular mechanisms and the pathway that are modulated, we have compared the bulk RNA expression profile of spinal cord from one month old wild type (WT) mice and MitoCharc1 transgenic mice (B6;D2-Tg(Eno2-MFN2*R94Q)L51Ugfm/J) which encode the mutant human MFN2*R94Q under the neuron specific rat enolase (Eno2) promoter, as potential mouse model to test the therapeutic approach. We performed gene expression profiling analysis using data (RNA-seq) obtained from 4 wild type mice and 8 MitoCharch1 transgenic mice at one time point.
2023-11-29 | GSE201264 | GEO
Project description:Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis¬. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations in the HARS catalytic domain are associated with Charcot Marie Tooth Disease Type 2W (CMT2W), while anticodon-binding domain mutations cause Usher Syndrome Type IIIB (USH3B). We use yeast as a model system to study disease-causing HARS mutations (V133F, V155G, Y330C, S356N) associated with CMT2W, and Y454S, associated with USH3B. All human HARS variants complemented genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, result in reduced growth. HARS V155G and S356N cause accumulation of insoluble proteins and mistranslation in yeast, and the growth defect of these mutants was rescued by histidine addition to the growth media, restoring the soluble proteome. V133F and Y330C, on the other hand, lead to decreased HARS abundance. Histidine supplementation further reduced viability in yeast expressing V133F and Y330C, and lead to insoluble protein accumulation, indicating histidine toxicity associated with these mutants. Because histidine is in clinical trials as treatment for USH3B, our data will inform future treatment options for these as well as CMT patients, where histidine supplementation may either have a toxic or compensating effect dependingon the nature of the causative HARS variant.
2023-03-10 | PXD034865 | Pride
Project description:Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase is associated with Charcot-Marie-Tooth neuropathy
| PRJNA515840 | ENA