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Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3

ABSTRACT: Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3

PROVIDER: PRJNA1227535 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32472665_1.fastq.gz	Fastqsanger.gz
	SRR32472665_2.fastq.gz	Fastqsanger.gz
	SRR32472666_1.fastq.gz	Fastqsanger.gz
	SRR32472666_2.fastq.gz	Fastqsanger.gz
	SRR32472667_1.fastq.gz	Fastqsanger.gz

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Genetics of Charcot-Marie-Tooth Disease

Project description:Genetics of Charcot-Marie-Tooth Disease

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Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3

Project description:Biallelic loss of expression/function variants in MTMR5/SBF1 cause the inherited peripheral neuropathy Charcot-Marie-Tooth (CMT) Type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying CMT4B3, and despite its severe clinical presentation, currently no disease modifying therapies. A key barrier to the study of CMT4B3 is the lack of pre-clinical models that recapitulate the clinical and pathologic features of the disease. To address this barrier, we generated a zebrafish CRISPR/Cas9 mutant line with a full gene deletion of mtmr5. Resulting homozygous deletion zebrafish are born at normal Mendelian ratios and have preserved motor function. However, starting by 10 days-post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume. These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination, changes reminiscent of the nerve pathology in human CMT4B3. Importantly, RNA sequencing from brain-enriched samples identifies novel disease pathways including transcriptional changes in genes responsible for neurogenesis, chromatin remodeling/organization, and synaptic membrane homeostasis. Overall, our mtmr5 knockout zebrafish mirror genetic, clinical, and pathologic features of human CMT4B3. As such, it represents a first pre-clinical model to phenocopy the disease, and an ideal tool for future studies on disease pathomechanism(s) and therapy development.

2025-03-03 | GSE290354 | GEO

Genomic Studies in Charcot-Marie-Tooth Disease

Project description:Genomic Studies in Charcot-Marie-Tooth Disease

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Genomic Studies in Charcot-Marie-Tooth Disease

Project description:Genomic Studies in Charcot-Marie-Tooth Disease

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Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth Disease

Project description:Aminoacyl-tRNA synthetases are indispensable enzymes in all cells, ensuring the correct pairing of amino acids to their cognate tRNAs to maintain translational fidelity. Autosomal dominant mutations V133F and Y330C in histidyl-tRNA synthetase (HARS) cause the genetic disorder Charcot-Marie-Tooth type 2W (CMT2W). HARS V133F and Y330C cause mistranslation as validated by mass spectrometry and growth defects that persist with histidine supplementation. The growth defects and translation fidelity for both V133F and Y330C mutants were rescued by supplementation with human tRNAHis in a humanized yeast model.

2025-05-06 | PXD050340 | Pride

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase is associated with Charcot-Marie-Tooth neuropathy

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

Hyper-activation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2

Project description:Hyper-activation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2

| PRJNA377238 | ENA

Combined RNAinterfering and gene therapy targeting MFN2 for the treatment of Charcot-Marie-Tooth type 2A

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

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

Project description:Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

| PRJNA1057744 | ENA

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

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

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