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A novel model of demyelination and remyelination in a GFP-transgenic zebrafish.

ABSTRACT: Demyelinating diseases consist of a variety of autoimmune conditions in which the myelin sheath is damaged due to genetic and/or environmental factors. During clinical treatment, some patients undergo partial remyelination, especially during the early disease stages. However, the mechanisms that regulate demyelination remain unclear. The myelin structure, myelin formation and myelin-related gene expression are highly conserved between mammals and zebrafish. Therefore, the zebrafish is an ideal model organism to study myelination. In this study, we generated a transgenic zebrafish Tg(mbp:nfsB-egfp) expressing a fusion protein composed of enhanced green fluorescent protein (EGFP) and NTR from the myelin basic protein (mbp) promoter. Tg(mbp:nfsB-egfp) expressed NTR-EGFP reproducibly and hereditarily in oligodendrocytes along the spinal cord. Treatment of zebrafish larvae Tg(mbp:nfsB-egfp) with metronidazole (Mtz) resulted in the selective ablation of oligodendrocytes and led to demyelination, accompanied by behavioral changes, including decreased total movement distance, velocity, total movement time and fast movement time. After withdrawal of Mtz for a seven day recovery period, the expression of EGFP and MBP protein was observed again which indicates remyelination. Additionally, locomotor capacity was restored. Collectively, Tg(mbp:nfsB-egfp), a heritable and stable transgenic line, provides a novel, powerful tool to study the mechanisms of demyelination and remyelination.

SUBMITTER: Fang Y

PROVIDER: S-EPMC4295166 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A novel model of demyelination and remyelination in a GFP-transgenic zebrafish.

Fang Yangwu Y Lei Xudan X Li Xiang X Chen Yanan Y Xu Fei F Feng Xizeng X Wei Shihui S Li Yuhao Y

Biology open 20141219 1

Demyelinating diseases consist of a variety of autoimmune conditions in which the myelin sheath is damaged due to genetic and/or environmental factors. During clinical treatment, some patients undergo partial remyelination, especially during the early disease stages. However, the mechanisms that regulate demyelination remain unclear. The myelin structure, myelin formation and myelin-related gene expression are highly conserved between mammals and zebrafish. Therefore, the zebrafish is an ideal m ...[more]

PMID: 25527642

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Project description:BACKGROUND:Various studies by MRI exhibit that the corpus callosum (CC) is the most vulnerable to cuprizone administration, detecting the demyelination and remyelination process using different MRI parameters are, however, lacking. PURPOSE:To investigate the sensitivity of multiparametric MRI both in vivo and ex vivo for demyelination and remyelination. STUDY TYPE:Prospective. ANIMAL MODEL:A cuprizone mice model with an age-matched control group (n = 5), 4-week cuprizone exposure group followed by 9-week on a normal diet (n = 6), and a 13-week cuprizone exposure group (n = 6). FIELD STRENGTH/SEQUENCE:3D gradient recalled echo, T2 -weighted, and diffusion tensor imaging (DTI) at 7.0T and 9.4T. ASSESSMENT:Quantification of DTI metrics, quantitative susceptibility mapping (QSM), and T2 -weighted imaging intensity in major white matter bundles. STATISTICAL TESTS:Nonparametric permutation tests were used with a cluster-forming threshold as 3.09 (equivalent to P = 0.001), and the significant level as P = 0.05 with family-wise correction. RESULTS:In vivo susceptibility values increased from -11.7 to -0.7 ppb (P < 0.001) in CC and from -13.7 to -5.1 ppb (P < 0.001) in the anterior commissure (AC) after the 13-week cuprizone exposure. Ex vivo susceptibility values increased from -25.4 to 7.4 ppb (P < 0.001) in CC and from -41.6 to -15.8 ppb (P < 0.001) in AC. Susceptibility values showed high variations to demyelination for in vivo studies (94.0% in CC, 62.8% in AC). Susceptibility values exhibited higher variations than radial diffusivity for ex vivo studies (129.1% vs. 28.3% in CC, 62.0% vs. 25.0% in AC). In addition to the differential susceptibility variations in different white matter tracts, intraregional demyelination variation was also present not only in CC but also in the AC area by voxel-based analysis. DATA CONCLUSION:QSM is sensitive to the demyelination process of cuprizone exposure, which can be a complementary technique to conventional T2 -weighted images and DTI metrics. LEVEL OF EVIDENCE:2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1852-1865.

Project description:The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.

Dataset Information

A novel model of demyelination and remyelination in a GFP-transgenic zebrafish.

Publications

A novel model of demyelination and remyelination in a GFP-transgenic zebrafish.

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