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The role of LRRK2 in cell signalling

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© 2019 The Author(s). Parkinson’s disease (PD) is a common late-onset neurodegenerative disorder known primarily for its motor features. Mutations and risk variants in LRRK2 cause familial and idiopathic forms of PD. Mutations segregating with disease are found in the LRRK2 GTPase and kinase domains, affecting catalytic activity and protein–protein interactions. This likely results in an overall gain of LRRK2 cell signalling function contributing to PD pathogenesis. This concept supports the development of LRRK2 kinase inhibitors as disease-modifying treatments, at least for a subset of patients. However, the function of LRRK2 as a cell signalling protein with two catalytic and several protein–protein interaction domains is highly complex. For example, LRRK2 plays important roles in several inflammatory diseases, raising the possibility that it may mediate immune responses in PD. Consistently, LRRK2-mediated cell signalling was not only shown to be important for neuronal function, including neuronal development and homeostasis, but also for peripheral and central immune responses. The catalytic activity of LRRK2 is regulated by autophosphorylation, protein monomer/dimer cycling, and upstream kinases and GTPases, affecting its subcellular localisation and downstream signalling. Part of LRRK2-mediated signalling is likely facilitated by Rab protein phosphorylation, affecting primarily membrane trafficking, including vesicle release at the trans-Golgi network. However, LRRK2 also displays intrinsic GTPase activity and functions as a signalling scaffold. As an example, LRRK2 was suggested to be part of the NRON complex and β-catenin destruction complex, inhibiting NFAT and canonical Wnt signalling, respectively. In summary, continuous research into LRRK2 signalling function contributes to novel diagnostic and therapeutic concepts in PD.

Publication metadata

Author(s): Harvey K, Outeiro TF

Publication type: Review

Publication status: Published

Journal: Biochemical Society Transactions

Year: 2019

Volume: 47

Issue: 1

Pages: 197-207

Print publication date: 01/02/2019

Online publication date: 21/12/2018

Acceptance date: 19/11/2018

ISSN (print): 0300-5127

ISSN (electronic): 1470-8752

Publisher: Portland Press Ltd


DOI: 10.1042/BST20180464

PubMed id: 30578345