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Leucine‐rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase‐3β
Author(s) -
Kawakami Fumitaka,
Shimada Naoki,
Ohta Etsuro,
Kagiya Go,
Kawashima Rei,
Maekawa Tatsunori,
Maruyama Hiroko,
Ichikawa Takafumi
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12579
Subject(s) - lrrk2 , phosphorylation , gsk 3 , kinase , neurite , microbiology and biotechnology , regulator , gsk3b , leucine rich repeat , chemistry , glycogen synthase , biology , biochemistry , in vitro , gene , mutation
Leucine‐rich repeat kinase 2 ( LRRK 2) has been identified as the causal molecule for autosomal‐dominant Parkinson's disease ( PD ). Experimental evidence indicates that LRRK 2 may play an important role in the pathology induced by abnormal phosphorylation of tau. In the present study, we demonstrated that LRRK 2 directly associates with GSK ‐3β, and that this interaction enhances the kinase activity of GSK ‐3β. Furthermore, we found that LRRK 2‐mediated activation of GSK ‐3β induces high phosphorylation of tau at Ser396 in SH ‐ SY 5Y cells. From our present findings, we conclude that LRRK 2 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 LRRK 2 is detected in tau‐positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD , LRRK 2‐stimulated phosphorylation of tau by GSK ‐3β may be involved in development of pathological features in the initial stage of PD . Structured digital abstractLRKK2 physically interacts with GSK-3B by anti bait coimmunoprecipitation ( View interaction ) LRRK2 physically interacts with GSK-3B by anti tag coimmunoprecipitation ( View interaction ) LRRK2 binds to GSK-3B by pull down ( View interaction ) GSK-3B physically interacts with LRRK2 and TAU by pull down ( View interaction )