title: LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission.
abstract: Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27(Kip1) expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27(Kip1)-cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do 200-702, Republic of Korea.
authors.forename: J-E
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do 200-702, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Ryu
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do 200-702, Republic of Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do 200-702, Republic of Korea.
authors.forename: T-C
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D034281:Dynamins / Q000502:physiology*; D015870:Gene Expression; D054461:Lim Kinases / Q000502:physiology*; D008297:Male; D063154:Mitochondrial Dynamics; D009336:Necrosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D013226:Status Epilepticus / Q000473:pathology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C530106:Ccnd1 protein, rat; C493962:Cdkn1b protein, rat; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054461:Lim Kinases; C490644:Limk2 protein, rat; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C519851:Dnm1l protein, rat; D034281:Dynamins