Contributions
Abstract: P1778
Type: Poster Sessions
Abstract Category: N/A
Regeneration of myelin is mediated by oligodendrocyte progenitor cells (OPCs), an abundant stem cell population in the CNS and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the central nervous system (CNS) underlies a number of neurological diseases, including multiple sclerosis (MS) and diverse genetic diseases. Using high throughput chemical screening approaches, we and others have identified small molecules that stimulate oligodendrocyte formation from OPCs and functionally enhance remyelination in vivo. Here we show a broad range of these pro-myelinating small molecules--including benztropine, clemastine, miconazole, and many others--function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to OPCs in purified form while analogous sterols lacking this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism-of-action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics (in press, Nature).
Disclosure: Drew Adams is a co-founder, director, and consultant to Convelo Therapeutics, Inc. which seeks new treatments for diseasesof myelin; this work was supported by National Institutes of Health grant NS095280 (R.H.M., P.J.T), Conrad N. Hilton Foundation Pilot Innovator in MS Award (D.J.A.), Mallinckrodt Foundation Grant Award (D.J.A), philanthropic support from the Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families, and unrestricted support from the CWRU School of Medicine.
Abstract: P1778
Type: Poster Sessions
Abstract Category: N/A
Regeneration of myelin is mediated by oligodendrocyte progenitor cells (OPCs), an abundant stem cell population in the CNS and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the central nervous system (CNS) underlies a number of neurological diseases, including multiple sclerosis (MS) and diverse genetic diseases. Using high throughput chemical screening approaches, we and others have identified small molecules that stimulate oligodendrocyte formation from OPCs and functionally enhance remyelination in vivo. Here we show a broad range of these pro-myelinating small molecules--including benztropine, clemastine, miconazole, and many others--function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to OPCs in purified form while analogous sterols lacking this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism-of-action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics (in press, Nature).
Disclosure: Drew Adams is a co-founder, director, and consultant to Convelo Therapeutics, Inc. which seeks new treatments for diseasesof myelin; this work was supported by National Institutes of Health grant NS095280 (R.H.M., P.J.T), Conrad N. Hilton Foundation Pilot Innovator in MS Award (D.J.A.), Mallinckrodt Foundation Grant Award (D.J.A), philanthropic support from the Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families, and unrestricted support from the CWRU School of Medicine.