Wnt and Ca2+ signalling changes in LRRK2 Parkinson's disease models

Abstract

ObjectiveExamination of the influence of leucine‐rich repeat kinase 2 (LRRK2) on Wnt and Ca2+ signalling changes in Parkinson's disease.BackgroundMutations in LRRK2 are a major cause of Parkinson's disease. Changes in LRRK2 activity were shown to cause alterations in several cell signalling pathways. Wnt and Ca2+ signalling changes are some of the most reproducible reported observations to date. LRRK2 was shown to modulate Ca2+‐dependent immune responses, autophagy and mitochondrial function. In addition, LRRK2 modulated canonical Wnt signalling was shown to be affected in opposite ways by protective and pathogenic genetic Parkinson's disease variants, suggesting a clear correlation between Wnt signalling activity and neurodegenerative disease. This suggests the prospect of targeting Wnt signalling pathways to slow or halt the progression of Parkinson's disease.MethodsUse of LRRK2 knockout and G2019S knock‐in models to conduct functional Wnt signalling assays. We introduced lentiviral biosensors into mouse brains to record Wnt and Ca2+ cell signalling changes in the brains of live animals from one week to six months of age using an advanced imaging technology (IVIS).ResultsHere, we present the analysis of Wnt and Ca2+ signalling activity using the exciting new technology of tissue‐targeted delivery of lentiviruses containing a transcription factor activated luciferase reporter to newborn mice. This allows quantification of transcription factor activity over the lifetime of an animal. We compare wild type mice with LRRK2 knockout mice and with mice harbouring the most prevalent familial LRRK2 G2019S mutation. Our data collectively support the idea of LRRK2 as a modulator of Wnt and Ca2+ signalling.ConclusionsIncreasing our understanding of the role of LRRK2 in Wnt and Ca2+ signalling pathways during neuronal development and aging might contribute to the generation of novel PD treatments targeting early events in the pathogenesis of PD. Decrease in Wnt signalling activity has previously been linked to neurodegeneration and provides therefore a plausible mechanism and a good therapeutic target in the Parkinson's disease process.Support or Funding InformationMedical Research Council, Wellcome Trust