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Neurotherapeutics

, Volume 11, Issue 4, pp 738–750 | Cite as

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

  • Iakov N. Rudenko
  • Mark R. CooksonEmail author
Review

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.

Key Words:

Parkinson’s disease kinase inhibitors GTPase vesicular trafficking cytoskeleton treatment. 

Notes

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.

Competing Interests

The authors have no competing interests.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2014_284_MOESM1_ESM.pdf (1.2 mb)
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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. (outside the U.S.) 2014

Authors and Affiliations

  1. 1.Cell Biology and Gene Expression Section, Laboratory of NeurogeneticsNational Institute on Aging, National Institutes of HealthBethesdaUSA

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