Duke University has received a USD 1.81 million NIH RF1 grant from the National Institute of Neurological Disorders and Stroke to investigate how LRRK2 kinase signaling changes during the progression of Parkinson's disease and Alzheimer's disease, with the aim of identifying biomarkers that predict disease severity and defining patient populations most likely to respond to LRRK2-targeted therapies.
LRRK2 as a progression biomarker
The project, led by Andrew B. West in Duke's Department of Pharmacology, centers on measuring phosphorylated Rab10, the primary substrate of LRRK2 kinase activity, in serum and cerebrospinal fluid from deeply phenotyped longitudinal cohorts of Parkinson's and Alzheimer's patients and neurologically normal controls. Preliminary cross-sectional data from the team suggest elevated pRab10 levels associate with worse Parkinson's disease severity, and post-mortem analyses have identified aberrant pRab10 accumulations in both Parkinson's and Alzheimer's brain tissue. The grant will extend those observations into a longitudinal framework, providing what the investigators describe as the first large-scale effort to track LRRK2 signaling changes over the course of neurodegeneration in humans. Whole blood transcriptomic profiles and genomic data will be interrogated alongside the biofluid measurements to identify factors driving LRRK2 activity, and pathologically staged brain tissue will be analyzed in parallel with mouse models carrying progressive tau and alpha-synuclein pathology.
Translational context
LRRK2 has been established as a cause of familial Parkinson's disease through pathogenic missense mutations and as a risk factor for idiopathic Parkinson's disease through genome-wide association studies implicating promoter variants. The kinase operates within the endolysosomal system, phosphorylating Rab GTPases to regulate vesicle trafficking and cellular responses. Post-mortem data indicate that most LRRK2 mutation carriers harbor mixed pathology including 3R/4R tauopathy, amyloid beta changes, and Lewy body deposition, placing LRRK2 at an intersection relevant to both Parkinson's and Alzheimer's biology. The Duke program is designed to determine whether LRRK2 signaling levels in accessible biofluids can serve as progression-sensitive readouts, which would have direct utility for stratifying patients in future therapeutic trials of LRRK2 kinase inhibitors, several of which are in clinical development across the industry.