title: RNAi screening identifies GSK3β as a regulator of DRP1 and the neuroprotection of lithium chloride against elevated pressure involved in downregulation of DRP1.
abstract: Elevated intraocular pressure (IOP) is considered as the major risk factor for the loss of retinal ganglion cells (RGCs) and their axons in glaucoma. Emerging evidence suggests elevated IOP can induce Drp1 upregulation and mitochondrial fission, which is involved in cell death. However, the underlying mechanism for these effects remains unknown. The present study used RNAi screening to investigate the effects of 24 kinases associated with mitochondrial activities on DRP1 expression under hydrostatic pressure. We identified, for the first time, that glycogen synthase kinase 3 beta (GSK3β) knockdown suppressed the upregulation of DRP1 induced by elevated pressure. Use of the pharmacological inhibitor of GSK3β inhibitor, lithium chloride (LiCl), confirmed this result. Furthermore, we demonstrated that one of the mechanisms of lithium chloride neuroprotection might be via inhibition of mitochondrial fission through downregulation of Drp1.
authors.affiliation: Eye & ENT Hospital, Fudan University, 200032, China; Shanghai Key Laboratory of Visual Impairment and Restoration, 200032, China.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Wu
authors.forename: Sheng-Hai
authors.initials: SH
authors.lastname: Zhang
authors.forename: Feng-Juan
authors.initials: FJ
authors.lastname: Gao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lei
authors.forename: Xin-Ya
authors.initials: XY
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Shu-Jie
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Xing-Huai
authors.initials: XH
authors.lastname: Sun
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006874:Hydrostatic Pressure; D018021:Lithium Chloride / Q000494:pharmacology*; D063154:Mitochondrial Dynamics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D034622:RNA Interference; D017208:Rats, Wistar; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C519851:Dnm1l protein, rat; D034281:Dynamins; D018021:Lithium Chloride
keywords: DRP1; Elevated hydrostatic pressure; GSK3β; Glaucoma; Mitochondrial fission