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

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

PROVIDER: PRJNA830527 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18862664_1.fastq.gz	Fastqsanger.gz
	SRR18862664_2.fastq.gz	Fastqsanger.gz
	SRR18862665_1.fastq.gz	Fastqsanger.gz
	SRR18862665_2.fastq.gz	Fastqsanger.gz
	SRR18862666_1.fastq.gz	Fastqsanger.gz

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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

RNA sequencing of MShef11 WT, MFN2R94Q/+, MFN2 R94Q/R94Q differentiated to limb innervating motor neurons

Project description:We have generated CRISPR edited versions of hESC line MShef11 to produce MFN2 R94Q/+ and MFN2 R94Q/R94Q lines as a model for Charcot Marie Tooth Disease (CMT) 2A. This were differentiated to limb innervating motor neurons, the predominantly affected cell time in CMT2A and RNA was examined to investigate differences in cell lines.

2022-07-28 | E-MTAB-10831 | biostudies-arrayexpress

Genetics of Charcot-Marie-Tooth Disease

Project description:Genetics of Charcot-Marie-Tooth Disease

| PRJNA382008 | ENA

Genomic Studies in Charcot-Marie-Tooth Disease

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

| PRJNA1006093 | ENA

Genomic Studies in Charcot-Marie-Tooth Disease

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

| PRJNA1006094 | ENA

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

Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2).

Project description:BackgroundCharcot-Marie-Tooth neuropathies are a group of genetically heterogeneous diseases of the peripheral nervous system. Mutations in the MFN2 gene have been reported as the primary cause of Charcot-Marie-Tooth disease type 2A.MethodsPatients with the clinical diagnosis of Charcot-Marie-Tooth type 2 were screened using single strand conformation polymorphism (SSCP). All DNA samples showing band shifts in the SSCP analysis were amplified from genomic DNA and cycle sequenced.ResultsWe analyzed a total of 73 unrelated patients with a clinical diagnosis of CMT 2. Overall, novel mutations were detected in 6 patients. c.380G>T (G127V), c.1128G>A (M376I), c.1040A>T (E347V), c.1403G>A (R468H), c.2113G>A (V705I), and c.2258_2259insT (L753fs).ConclusionWe confirmed a significant role of mutations in MFN2 in the pathogenesis of Charcot-Marie-Tooth disease type 2.

| S-EPMC1524942 | biostudies-literature

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

MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A.

Project description:Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser378 Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94→Gln94 and MFN2 Thr105→Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.

| S-EPMC6109362 | biostudies-literature

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