Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination.

IF 10.6 1区 医学 Q1 CLINICAL NEUROLOGY
Brain Pub Date : 2025-01-06 DOI:10.1093/brain/awae378
Bing Han, Ming-Yue Bao, Qing-Qing Sun, Rui-Ning Wang, Xin Deng, Kun Xing, Feng-Lin Yu, Yan Zhang, Yue-Bo Li, Xiu-Qing Li, Na-Nan Chai, Gai-Xin Ma, Ya-Na Yang, Meng-Yuan Tian, Qian Zhang, Xing Li, Yuan Zhang
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引用次数: 0

Abstract

Myelin injury occurs in brain ageing and in several neurological diseases. Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPARγ in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPARγ and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood. Here, we identify PPARγ as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination/remyelination. Administration of pharmacological agonists of PPARγ not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPARγ function, either through the specific knockout of PPARγ in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPARγ agonists. At a mechanistic level, PPARγ induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination. In conclusion, our evidence reveals that PPARγ is a positive regulator of endogenous OPC differentiation and CNS myelination/remyelination and suggests that PPARγ and/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.

核受体PPARγ靶向GPNMB促进少突胶质细胞发育和髓鞘再生。
髓磷脂损伤发生在脑老化和一些神经系统疾病中。自发性髓鞘再生失败是由于中枢神经系统脱髓鞘病变中少突胶质前体细胞(OPCs)未充分分化为成熟的髓鞘形成少突胶质细胞。越来越多的证据表明,过氧化物酶体增殖物激活受体γ (PPARγ)是中枢神经系统损伤和修复的主要守门人,并在各种神经退行性疾病中发挥重要的调节作用。尽管研究表明PPARγ在体外少突胶质细胞发生中的积极作用,但PPARγ在细胞内的作用以及在体内参与OPC发育和中枢神经系统髓鞘再生过程的分子机制尚不清楚。在这里,我们发现PPARγ在中枢神经系统脱髓鞘病变中积累的功能失调的OPCs中是一个富集的转录因子。其表达在OPC分化和髓鞘形成过程中增加,与中枢神经系统脱髓鞘/再髓鞘形成过程密切相关。在铜酮和溶血磷脂酰胆碱诱导的脱髓鞘模型中,给药PPARγ药物激动剂不仅促进OPC分化和中枢神经系统髓鞘形成,而且显著增加髓鞘再生。相比之下,PPARγ功能的衰减,无论是通过体内少突胶质细胞中PPARγ的特异性敲除,还是通过其在体外的抑制,都会导致OPC成熟减少,髓磷脂生成受阻,PPARγ激动剂的治疗效果降低。在机制水平上,PPARγ通过直接靶向糖蛋白非转移性黑色素瘤蛋白B (GPNMB)诱导髓鞘修复,GPNMB是一种新的调节因子,可驱动OPCs分化为少突胶质细胞,促进出生后小鼠发育中的中枢神经系统的髓鞘形成,并增强小鼠的脱髓鞘再生。总之,我们的证据表明,PPARγ是内源性OPC分化和中枢神经系统髓鞘形成/再髓鞘形成的积极调节因子,并表明PPARγ和/或其下游传感器(GPNMB)可能是中枢神经系统再生治疗的候选药理学靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Brain
Brain 医学-临床神经学
CiteScore
20.30
自引率
4.10%
发文量
458
审稿时长
3-6 weeks
期刊介绍: Brain, a journal focused on clinical neurology and translational neuroscience, has been publishing landmark papers since 1878. The journal aims to expand its scope by including studies that shed light on disease mechanisms and conducting innovative clinical trials for brain disorders. With a wide range of topics covered, the Editorial Board represents the international readership and diverse coverage of the journal. Accepted articles are promptly posted online, typically within a few weeks of acceptance. As of 2022, Brain holds an impressive impact factor of 14.5, according to the Journal Citation Reports.
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