Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic.
Bottom Line: The burden that Parkinson's disease (PD) exacts on the population continues to increase year after year.The leucine-rich repeat kinase 2 (LRRK2) gene was identified in PD genetic studies and offers new hope for novel therapeutic approaches.The evidence linking LRRK2 kinase activity to PD susceptibility is presented, as well as seminal discoveries relevant to the prosecution of LRRK2 kinase inhibition.
Affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.Show MeSH
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Mentions: Kinase-activating effects of LRRK2 mutations could be caused by many factors. Based on the distribution of pathogenic mutations across the LRRK2 ROC, COR, and kinase domain (Fig. 2A), it is not surprising that different mutations have been postulated to affect kinase activity in different ways (Fig. 3). The most common LRRK2 mutation, G2019S, up-regulates kinase activity in a fundamental way that is revealed through every (published) assay. However, there are no other pathogenic LRRK2 mutations that enjoy this relationship. In some experimental settings, pathogenic LRRK2 mutations, such as R1441C, Y1699C, and I2020T, fail to distinguish LRRK2 kinase-associated activities from wild-type (WT) baselines, whereas, in other experiments, the mutations up-regulate kinase activities. Many of the initial controversies can be explained through a more detailed dissection of kinase activation and kinetics. Part of the problem is that experimental paradigms that describe LRRK2 kinase activity often rely on underlying assumptions that may confound interpretation when evaluating the effect of pathogenic mutations.
Affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.