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Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway

Hubler, Zita
http://orcid.org/0000-0003-0991-6229
http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Genetics.
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.
Drew Adams, Ph.D. (Advisor)
201 p.
Biochemistry; Chemistry; Neurobiology; Pharmaceuticals
oligodendrocyte; cholesterol; sterols; myelin; remyelination; multiple sclerosis; small-molecules; High-throughput screening; lanosterol; zymosterol; epoxycholesterol

Recommended Citations

Citations

  • Hubler, Z. (2020). Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819

    APA Style (7th edition)

  • Hubler, Zita. Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway. 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819.

    MLA Style (8th edition)

  • Hubler, Zita. "Enhancing Oligodendrocyte Formation via Inhibition of the Cholesterol Biosynthesis Pathway." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1595612178572819

    Chicago Manual of Style (17th edition)

case1595612178572819
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.