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: There are dozens of common nonsynonymous variants scattered throughout the LRRK2 gene in various populations and individuals (http://www.uniprot.org/uniprot/Q5S007) and, possibly, hundreds of rare or idiosyncratic variants. Only a minority of these variants are linked to PD. As yet, there is no biochemical assay, no definitive molecular biology test, to conclusively demonstrate the pathogenicity of a particular variant. Pathogenic mutations in LRRK2 (listed in Fig. 2A) are identified solely by their ability to segregate with disease in families. Idiosyncratic variants, no matter their identity or biochemical effects, cannot be interpreted as pathogenic without strong familial data that generally rely on DNA analysis from more than 5 affected subjects and at least as many unaffected subjects.
Affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.