Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs. Issue 10 (20th October 2022)

• Record Type: Journal Article
• Authors: Häberlein, Felix; Mingardo, Enrico; Merten, Nicole; Schulze Köhling, Nina-Katharina; Reinoß, Philip; Simon, Katharina; Japp, Anna; Nagarajan, Bhuvaneswari; Schrage, Ramona; Pegurier, Cecile; Gillard, Michel; Monk, Kelly R.; Odermatt, Benjamin; Kostenis, Evi; Gomeza, Jesus
• Is Part Of: Cell chemical biology. Volume 29:Issue 10(2022)
• Page Start: 1541
• Page End: 1555.e7
• Publication Date: 2022-10-20
• Subjects: G-protein-coupled receptor -- GPCR -- GPR17 -- oligodendrocyte -- demyelinating disease -- signal transduction -- zebrafish -- humanized animal model -- CNS; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.08.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches. Here we explore the experimental power of humanized zebrafish to foster the identification of pro-remyelination compounds via specific inhibition of GPR17. Using biochemical and imaging techniques, we visualize the expression of zebrafish ( zf )- gpr17 during the distinct stages of oligodendrocyte development, thereby demonstrating species-conserved expression between zebrafish and mammals. We also demonstrate species-conserved function of zf-Gpr17 using genetic loss-of-function and rescue techniques. Finally, using GPR17 -humanized zebrafish, we provide proof of principle for in vivo analysis of compounds acting via targeted inhibition of human GPR17. We anticipate that GPR17 -humanized zebrafish will markedly improve the search for effective pro-myelinating pharmacotherapies. Graphical abstract: Highlights: Gpr17 expression and function in oligodendrocytes are conserved from zebrafish to mammals Human (h)-GPR17 efficiently replaces the zebrafish ortholog in the in vivo context An h-GPR17 antagonist mimics the gpr17 -null fish phenotype in GPR17-humanized zebrafish Proof of principle of GPR17-humanized zebrafish for pro-remyelination drug discovery Abstract : The identification of drugs that promote remyelination in patients with demyelinating diseases, such as multiple sclerosis, is in high demand. Häberlein et al. introduce a GPR17-humanized zebrafish as proof of principle that fosters in vivo identification of novel pro-remyelination compounds acting via targeted inhibition of human GPR17.