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Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

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Leucine-Rich Repeat Kinase 2 (LRRK2)

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 14))

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson’s disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity. Familial LRRK2 mutations share in common the capacity to induce neuronal toxicity in cultured cells. While the contribution of the frequent G2019S mutation, located within the kinase domain, to kinase activity and neurotoxicity has been extensively investigated, the contribution of GTPase activity has received less attention. The GTPase domain has been shown to play an important role in regulating kinase activity, in dimerization, and in mediating the neurotoxic effects of LRRK2. Accordingly, the GTPase domain has emerged as a potential therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. Many important mechanisms remain to be elucidated, including how the GTPase cycle of LRRK2 is regulated, whether GTPase effectors exist for LRRK2, and how GTPase activity contributes to the overall functional output of LRRK2. In this review, we discuss the importance of the GTPase domain for LRRK2-linked PD focusing in particular on its regulation, function, and contribution to neurotoxic mechanisms.

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Acknowledgments

The authors are grateful for funding support from the National Institutes of Health (R01 NS091719), the Swiss National Science Foundation (grant no. 31003A_144063), and the Van Andel Research Institute.

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The author declares no conflicts of interest.

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  1. Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, USA

    An Phu Tran Nguyen & Darren J. Moore

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Correspondence to Darren J. Moore .

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  1. Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece

    Hardy J. Rideout

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Nguyen, A.P.T., Moore, D.J. (2017). Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity. In: Rideout, H. (eds) Leucine-Rich Repeat Kinase 2 (LRRK2). Advances in Neurobiology, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-49969-7_4

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