LRRK2 signaling in the progression of Parkinson's disease and dementia

About This Grant

Summary Genetic studies implicate pathogenic missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene as a common cause of familial Parkinson's disease (PD). Independently, genome-wide association studies identify LRRK2 promoter variants important in idiopathic PD risk. LRRK2 protein signals within the endolysosomal system through phosphorylating Rab protein substrates, altering their function in different pathways and cell responses. Phosphorylation of the prominently expressed Rab10 substrate is absent in LRRK2 knockout mice, diminishes with LRRK2 kinase inhibition, and is upregulated with pathogenic LRRK2 mutations and LRRK2 activation. Genetic variants in non-coding regions in Rab10 are tied to Alzheimer's disease (AD) resilience, and pRab10 upregulation may be associated with tau aggregation in the brain. Post- mortem studies find most LRRK2 carriers harbor 3R/4R tauopathy and Aß changes, often with Lewy pathology. Evidence in models suggests LRRK2 signaling may promote α-synuclein and tau pathology and related inflammation responses. However, there is a paucity of data from humans related to the role of LRRK2 signaling in disease progression. The main goals of this application are to learn whether LRRK2 signaling changes in PD and AD predict disease severity, discover pathways tied to these changes, and how LRRK2 signaling changes in the brain manifest with progressive pathological depositions of α-synuclein and tau. To accomplish these goals, our work in the last decade has culminated in the development of ultra- sensitive single molecule array assays, capable of assessing, with great specificity and sensitivity, LRRK2 signaling in biobanked tissues and fluids. Our recent results, starting from cross-sections of PD patients and controls, suggest a possible association between high pRab10 levels and worse PD severity. Preliminary results in post-mortem brain tissues have identified possible aberrant pRab10 accumulations in PD and AD. Here we propose to fully leverage deeply phenotyped longitudinal cohorts of PD and AD patients, and neurologically normal controls, to measure LRRK2 signaling changes as they occur with disease progression, in both serum and CSF. These measures will provide some of the first well-powered insights into how LRRK2 signaling changes might predict disease outcomes. Whole blood transcriptomic profiles and genomic data will be interrogated for factors critical in driving LRRK2 signaling. In complement, pathologically staged PD and AD brain tissues will be analyzed for LRRK2 signaling changes, together with powerful mouse models that have predictable progressive tau and α-synuclein pathology. Through the proposed work, the first large-scale effort to understand LRRK2 signaling changes in the progression of PD and AD, we expect to uncover new pathobiological mechanisms that further implicate LRRK2 in idiopathic neurodegenerative diseases, and begin to define idiopathic patient populations more likely to benefit from LRRK2-targeted therapeutic approaches.