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Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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Neurotherapeutics

Abstract

Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson’s disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)–C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Acknowledgments

We thank Dr. Aleksandra Beilina for fruitful discussions.

Funding

This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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The authors have no competing interests.

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  1. Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Iakov N. Rudenko & Mark R. Cookson

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  1. Iakov N. Rudenko
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Correspondence to Mark R. Cookson.

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Rudenko, I.N., Cookson, M.R. Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications. Neurotherapeutics 11, 738–750 (2014). https://doi.org/10.1007/s13311-014-0284-z

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