Kinases as Targets for Parkinson's Disease: From Genetics to Therapy

Renee      Vancraenenbroeck; Evy      Lobbestael; Marc      De Maeyer; Veerle      Baekelandt; Jean-Marc      Taymans

Abstract

Intense research efforts are currently directed at elucidating the etiology of Parkinson's disease (PD). One approach that has begun to shed light on the PD pathogenic pathways is the identification of disease genes through genetic linkage or association studies. These studies have revealed that several kinases may be involved in PD, as some PD genes encode kinases themselves while other PD genes are found in the same cellular pathways as kinases. Two of these kinases stand out as potential drug targets for novel PD therapy, namely leucine rich repeat kinase 2 (LRRK2) and the alpha-synuclein (α-syn) phosphorylating polo-like kinase 2 (PLK2). Indeed, both α- syn and LRRK2 show genetic linkage as well as genetic association with PD, indicating their relevance to a large number of PD cases. Also, due to the dominant mode of α-syn and LRRK2 inheritance and based on current knowledge of LRRK2 and α-syn phosphorylation by PLK2, inhibition of LRRK2 and PLK2 may constitute a potential therapy for PD. Here we discuss the function of these kinases as well as progress in their validation as drug targets for the treatment of PD.

Keywords: Leucine rich repeat kinase 2, Polo like kinase 2, alpha-synuclein, PINK1, ROC-GTPase, Autophosphorylation, ROCO protein, D. melanogaster, enzyme linked immunosorbant assay, PLKS