title: Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3β.
abstract: Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). Experimental evidence indicates that LRRK2 may play an important role in the pathology induced by abnormal phosphorylation of tau. In the present study, we demonstrated that LRRK2 directly associates with GSK-3β, and that this interaction enhances the kinase activity of GSK-3β. Furthermore, we found that LRRK2-mediated activation of GSK-3β induces high phosphorylation of tau at Ser396 in SH-SY5Y cells. From our present findings, we conclude that LRRK2 may function as a novel enhancer for GSK-3β and as a physiological regulator of neurite outgrowth and axonal transport through regulation of the GSK-3β-mediated phosphorylation of tau at the cellular level. Since LRRK2 is detected in tau-positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD, LRRK2-stimulated phosphorylation of tau by GSK-3β may be involved in development of pathological features in the initial stage of PD.
authors.affiliation: Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kawakami
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimada
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ohta
authors.forename: Go
authors.initials: G
authors.lastname: Kagiya
authors.forename: Rei
authors.initials: R
authors.lastname: Kawashima
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Maekawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Maruyama
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ichikawa
mesh_terms: D015153:Blotting, Western; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Parkinson's disease (PD); Tau; glycogen synthase kinase-3β (GSK-3β); leucine-rich repeat kinase 2 (LRRK2); phosphorylation