Loss of PRMT5 Promotes PDGFRα Degradation during Oligodendrocyte Differentiation and Myelination

Calabretta, Sara; Vogel, Gillian; Yu, Zhenbao; Choquet, Karine; Darbelli, Lama; Nicholson, Thomas B.; Kleinman, Claudia L.; Richard, Stéphane

doi:10.1016/j.devcel.2018.06.025

Cited by 41 publications

(27 citation statements)

References 64 publications

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“…The present results showed that the expression levels of IL-1β and NLRP3 were decreased by clemastine (H1 receptor antagonist), but the expression of HH1R was unaffected and localized in the microglia. The OPCs include NG2 and PDGFR-α cells, which differentiate progressively in a multiprocess morphology and sequentially bind to anti-CNPase and anti-MBP antibodies [26][27][28]. Through differentiation and maturation, OPCs migrate to myelinated target axons to form myelin.…”

Section: Discussionmentioning

confidence: 99%

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Xie

et al. 2020

J Neuroinflammation

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Background: Microglia activation is associated with the development of hypoxic-ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI. Methods: A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. Interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher's protected least significant difference test. Results: Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1β and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1β and reverse hypomyelination by inhibiting the p38 signaling pathway. Conclusions: Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

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Section: Discussionmentioning

confidence: 99%

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Xie

et al. 2020

J Neuroinflammation

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“…The maturation of OPCs plays an important role in the myelination of targeting axons. Several transcription factors are involved in the maturation of OPCs, such as Olig2, Nkx2.2, which promotes the maturation of OPCs [28,29]. Rcent research has suggested that VCAM1 knockout mice exhibit reduced myelin thickness, VCAM1 contributes to the initiation of myelination [30].…”

Section: Discussionmentioning

confidence: 99%

Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

Xie¹,

Niu²,

Gao³

et al. 2020

Preprint

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Background Cardiac arrest can lead to a poor prognosis of the nervous system. Neuroinflammation plays an important role in hypoxic ischemic brain injury (HIBI). Regulation of inflammation via autophagy might be a suitable therapeutic target in HIBI. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated astrocytes via autophagy and improving axonal hypomyelination in HIBI.Methods A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, autophagy related protein and OPCs differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of astrocytes and OPCs were used to explore the link between astrocytes activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher’s protected least significant difference test.Results Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. Expression of LC3Ⅱ/Ⅰdecreased after astrocytic activation. Co-culture of astrocytes and OPCs with oxygen glucose deprivation treatment exhibited NLRP3/1β upregulation and PLP downregulation. Clemastine could downregulate NLRP3/1β and reverse hypomyelination by promoting the autophagy.Conclusions Clemastine could improve axonal hypomyelination by inhibiting astrocytes activation via promoting the autophagy in BCCAO rats, thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

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“…For instance, the E3 ubiquitin ligase MDM2 targets GSK2, inducing internalization of G protein coupled receptor 17 (GPR17) and promoting OL differentiation (Fumagalli et al, ). The ubiquitination of PDGF receptor and GPR37 by an E3 ubiquitin ligase is also beneficial for OL differentiation (Calabretta et al, ; Yang, Vainshtein, Maik‐Rachline, & Peles, ). Wnt signaling in OPCs and OLs is regulated by the ubiquitin‐dependent degradation of β‐catenin (Shimizu et al, ).…”

Section: Discussionmentioning

confidence: 99%

BRCA1/BRCA2‐containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine 63‐linked ubiquitination

Wang

Deneen

Tzeng

2019

Glia

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Oligodendrocytes (OLs) provide the myelin sheath surrounding axons that propagates action potentials in the central nervous system (CNS). The metabolism of myelinated membranes and proteins is strictly regulated in the OLs and is closely associated with OL differentiation and maturation. The ubiquitination‐associated proteasome and endosomal system have not yet been well studied during OL differentiation and maturation. Here, we determined the functions of the Lys63‐linked ubiquitination (K63Ub) and K63‐specific deubiquitination (DUB) systems regulated by BRCA1/BRCA2‐containing complex subunit 3 (BRCC3) during OL differentiation. The competitive inhibition of K63Ub by overexpression of mutant ubiquitin (K63R) in oligodendrocyte precursor cells (OPCs) indicated that the two major CNS myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), were upregulated in OLs derived from K63R OPCs. In contrast, the knockdown of BRCC3 (BRCC3‐KD) through the application of lentivirus‐mediated shRNA delivery system into OPCs suppressed OL differentiation by decreasing MBP expression and PLP production. Further immunoprecipitation assays revealed higher levels of sphingolipid GalC, MBP, and PLP, which were associated with K63Ub‐immunoprecipitants and detected in endosome/lysosomal compartments, in BRCC3‐KD OLs than those in OLs transfected with the scrambled shRNA (scramble OLs). The differentiation of OLs from BRCC3‐KD OPCs was impaired in the demyelinating corpus callosum of rats receiving a cuprizone‐containing diet. In the demyelinating tissues from human patients suffering from multiple sclerosis, we detected a decreased number of BRCC3‐expressing OLs at the lesion site, accompanied by a greater number of OLs expressing EEA1 and K63Ub at high levels. Altogether, the counterbalance of the K63Ub machinery and BRCC3‐triggered DUB machinery are important for the cellular trafficking of myelin proteins and OL differentiation.

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Loss of PRMT5 Promotes PDGFRα Degradation during Oligodendrocyte Differentiation and Myelination

Cited by 41 publications

References 64 publications

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

BRCA1/BRCA2‐containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine 63‐linked ubiquitination

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