HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model

Prior, Robert; Verschoren, Stijn; Vints, Katlijn; Jaspers, Tom; Rossaert, Elisabeth; Klingl, Yvonne E.; Silva, Alessio; Hersmus, Nicole; Damme, Philip Van; Bosch, Ludo Van Den

doi:10.1007/s12035-022-02782-x

Cited by 10 publications

(14 citation statements)

References 45 publications

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“…To investigate the role PMP22 has in cholesterol and lipid metabolism in more detail, we focused on the less severe C3 CMT1A mouse model. These C3 mice present a dysmyelinating phenotype early in development followed by an improvement in myelination (Prior et al, 2022;Verhamme et al, 2011), similar to the aforementioned partial developmental amelioration in the cholesterol biosynthesis and lipid metabolism pathways (Fig. 1c, d).…”

Section: Pmp22 Overexpression Causes Abnormal Lipid Metabolism In The...supporting

confidence: 66%

“…Harboring at least 7 copies of the yeast artificial chromosome containing the human PMP22 gene, the C22 mice display postnatal defects in myelination (Robaglia-Schlupp et al, 2002;Robertson et al, 1999;Verhamme et al, 2011). The spontaneous revertant of the C22 mouse, designated the C3 mouse model (Verhamme et al, 2011) contains 5 copies of the human PMP22 gene, as we reported previously (Prior et al, 2022). These mouse models, in addition to the transgenic CMT1A rat model (Fledrich et al, 2012) are the current gold standard in vivo models for CMT1A research.…”

Section: Introductionmentioning

confidence: 82%

“…Animals were kept and bred in the same conditions as described above. To verify the genotype and copy numbers of human PMP22, digital droplet PCR (ddPCR) was performed as previously described (Prior et al, 2022).…”

Section: Animalsmentioning

confidence: 99%

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Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Prior

Silva

Vangansewinkel

et al. 2023

Preprint

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Duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A) and is known to disrupt the lipid metabolism in myelinating Schwann cells by unknown mechanisms. By using two CMT1A mouse models overexpressing human PMP22, we discovered that PMP22 dose-dependently downregulates genes that are involved in lipid and cholesterol metabolism. Lipidomic analysis on CMT1A mouse sciatic nerves confirmed lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids. We observed similar lipidomic profiles and downregulation of genes associated with lipid metabolism in human CMT1A patient induced pluripotent stem cell-derived Schwann cell precursors (iPSC-SCPs). We confirmed these findings by demonstrating altered lipid raft dynamics and plasma membrane fluidity in CMT1A iPSC-SCPs. Additionally, we identified impaired cholesterol incorporation in the plasma membrane due to altered lipid storage homeostasis in CMT1A iPSC-SCPs, which could be modulated by changing the lipid composition of the cell culture medium. These findings suggest that PMP22 plays a role in regulating the lipid composition of the plasma membrane and lipid storage homeostasis. Targeting lipid metabolism may hold promise as a potential treatment for CMT1A patients.

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Section: Pmp22 Overexpression Causes Abnormal Lipid Metabolism In The...supporting

confidence: 66%

Section: Introductionmentioning

confidence: 82%

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Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Prior

Silva

Vangansewinkel

et al. 2023

Preprint

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“…Furthermore, the participation of MAPK-ERK1/2 and PI3K-AKT signaling pathways are essential to the formation and differentiation of nerve myelination. 36 Also, enrichment was found in metabolism-related pathways, and it is noteworthy that bone metabolism markers (such as parathyroid hormone) were reported to be correlated with CSVD burden. 23 Generally, pathway analysis suggested hypoxia and inflammation response in brain as well as metabolic disorders were significantly regulated by these DE miRNAs.…”

Section: Discussionmentioning

confidence: 98%

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease

Gao¹,

Yin²,

Wang³

et al. 2023

IJGM

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Background Cerebral small vessel disease (CSVD) with an insidious onset can cause overall neurological dysfunction and dementia, bringing a massive burden to society. However, the pathogenesis of CSVD is complex and reliable non-invasive biomarkers for diagnosis are still not available at present. Our study aimed to investigate abnormal exosomal miRNA patterns via microarray analysis and identify candidate biomarkers for CSVD. Methods We isolated exosomes from the plasma of all subjects and identified exosomes via currently universally accepted methods. The miRNAs were profiled through microarrays, and then the expression of selected differentially expressed miRNAs was validated through RT-PCR. GO and KEGG analysis predicted possible functions of differentially expressed miRNAs. Receiver operating characteristic (ROC) curve was employed to observe the diagnostic value of selective miRNAs. Finally, the relationship between the expression of miR-320e and the CSVD burden was analyzed. Results A total of 14 miRNAs displayed differential enrichment levels with |fold change|≥1.5 and p<0.05 through miRNA microarray analysis. The RT-PCR analysis validated that exosomal miR-320e was significantly downregulated in CSVD patients (p<0.0001). ROC curve analysis of exosomal miR-320e showed the area under the curve of 0.752. According to the multivariable analysis, miR-320e was an independent predictor of white matter hyperintensity ([aOR]= 0.452, 95% confidence interval [CI]= 0.258–0.792, p=0.006) and exhibited a negative correlation with the load of periventricular white matter hyperintensities (p=0.0021) and deep white matter hyperintensities (p=0.0018), respectively. In addition, it exhibited a negative correlation with total CSVD burden score (r=−0.276, p=0.001). Conclusion In our study, plasma exosomal miR-320e has a certain diagnostic value for CSVD, and a significant correlation with imaging burden of CSVD. Overall, exosomal miR-320e has the potential to be a novel biomarker for CSVD, but further research with a large sample size is necessary to assess its clinical utility.

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“…It would be interesting in future studies to test different Theophylline treatment paradigms, such as longer-term treatments or several treatment rounds, to potentially further improve (re)myelination and functional recovery, and to test the efficacy of Theophylline treatment in other models of demyelinating peripheral neuropathies. A recent study showed that treatment with an HDAC3 inhibitor could also improve function and myelination in another CMT1A mouse model [ 51 ]. Since HDAC3 inhibition and HDAC2 activation by Theophylline treatment act through different pathways, it would be interesting to test whether a combination treatment could have additive or synergistic effects in the induction of (re)myelination and functional recovery in demyelinating peripheral neuropathies.…”

Section: Discussionmentioning

confidence: 99%

Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

et al. 2022

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Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

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HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model

Cited by 10 publications

References 45 publications

Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease

Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

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