Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway

Bibliographic Details
Main Author:	Hubler, Zita
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2020
Subjects:	Biochemistry Chemistry Neurobiology Pharmaceuticals oligodendrocyte cholesterol sterols myelin remyelination multiple sclerosis small-molecules High-throughput screening lanosterol zymosterol epoxycholesterol
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case15956121785728192021-08-03T07:15:53Z Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway Hubler, Zita Biochemistry Chemistry Neurobiology Pharmaceuticals oligodendrocyte cholesterol sterols myelin remyelination multiple sclerosis small-molecules High-throughput screening lanosterol zymosterol epoxycholesterol Loss of myelin-producing oligodendrocytes in the central nervous system (CNS) underlies several neurological diseases, including multiple sclerosis. Demyelinating disorders lead to cognitive and motor deficits, yet there are no FDA-approved remyelinating therapeutics. In the CNS, oligodendrocyte progenitor cells (OPCs) give rise to oligodendrocytes, which are capable of regenerating myelin. To discover novel therapies for demyelinating disorders, we performed in vitro chemical-genetic screens in OPCs looking for small molecules that enhance oligodendrocyte formation and remyelination. We found that the vast majority of pro-myelinating small molecules identified function, not through their canonical targets, but instead converge upon enzymes in the cholesterol biosynthesis pathway: CYP51, sterol-14-reductase, or EBP. Genetic experiments show that depletion of CYP51 or EBP enhances oligodendrocyte formation independent of small molecule treatment. Likewise, evaluation of in vivo validated remyelinating compounds, identified by other labs, confirmed that inhibition of CYP51, sterol-14-reductase, and EBP is a dominant mechanism shared by dozens of small molecules that enhance oligodendrocyte formation. The accumulation of the 8,9-unsaturated sterol substrates of CYP51, sterol-14- reductase, and EBP is a critical mechanistic node of these pro-myelinating compounds. Multiple molecules that enhance 8,9-unsaturated sterol intermediate levels can regenerate functional myelin in vivo and a human cortical spheroid model. Evaluation of 8,9-unsaturated sterol structural variants revealed that 24,25-epoxycholesterol also promotes oligodendrocyte formation, despite lacking an 8,9-unsaturation. 24,25-epoxycholesterol accumulates upon partial inhibition of LSS in the cholesterol biosynthesis pathway through the epoxycholesterol shunt. Therefore, our work establishes the epoxycholesterol shunt and 24,25- epoxycholesterol as another sterol signaling axis regulating OPC differentiation and validates LSS as a druggable target for promoting oligodendrocyte formation. Overall, our findings establish a novel paradigm in which the cholesterol biosynthesis pathway can be leveraged to enhance the formation of new oligodendrocytes by inhibiting the enzymes LSS, CYP51, sterol-14-reductase, or EBP. We outline a unifying sterol-based mechanism of action for most known small molecule enhancers of oligodendrocyte formation. Ultimately, our work demonstrates that modulating the sterol landscape in OPCs can enhance the formation of oligodendrocytes and points to new therapeutic targets, potent inhibitors for these targets, and metabolite-based biomarkers to accelerate the development of optimal remyelinating therapeutics. 2020-09-07 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819 http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819 restricted--full text unavailable until 2022-08-14 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biochemistry Chemistry Neurobiology Pharmaceuticals oligodendrocyte cholesterol sterols myelin remyelination multiple sclerosis small-molecules High-throughput screening lanosterol zymosterol epoxycholesterol
spellingShingle	Biochemistry Chemistry Neurobiology Pharmaceuticals oligodendrocyte cholesterol sterols myelin remyelination multiple sclerosis small-molecules High-throughput screening lanosterol zymosterol epoxycholesterol Hubler, Zita Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
author	Hubler, Zita
author_facet	Hubler, Zita
author_sort	Hubler, Zita
title	Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
title_short	Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
title_full	Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
title_fullStr	Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
title_full_unstemmed	Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway
title_sort	enhancing oligodendrocyte formation via inhibition of the cholesterol biosynthesis pathway
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2020
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819
work_keys_str_mv	AT hublerzita enhancingoligodendrocyteformationviainhibitionofthecholesterolbiosynthesispathway
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Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway

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