Project Details
Projekt
LRRK2 as a target for the treatment of Parkinson’s disease
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 414868630
Small molecules inhibiting LRRK2 are promising new drug candidates to protect neurons against Parkinson’s disease (PD) pathology. However, PD is a heterogeneous neurodegenerative disorder consisting of multiple subtypes with patients differing widely in their symptoms and progression, making it very difficult for a clinical trial to detect an effective drug. Thus, biomarkers are urgently needed to identify patient subgroups that would respond to LRRK2 inhibitors as well as biomarkers of to monitor target engagement. In order to identify these biomarkers, it is first necessary to understand the mechanism by which LRRK2 affects neurodegeneration. Using neurons differentiated from induced pluripotent stem cells (iPSCs) from patients with mutant LRRK2 and isogenic mutation-corrected controls, we have developed one of the first robust neurodegenerative phenotypes using axonal trafficking, and this trafficking defect is completely rescued by treating with LRRK2 inhibitors. Using quantitative phospho-proteomics, we found that LRRK2 activity is associated with increased phosphorylation of microtubule associated proteins (MAPs), which leads to disruption of the cytoskeleton, causing axonal degeneration. It is likely that these changes are indirect since LRRK2 is expressed at very low levels, and many kinases are known to mediate MAP phosphorylation. Rab proteins have been shown to be directly phosphorylated by LRRK2 and have been linked to axonal trafficking, making them good candidate biomarkers for target engagement. Here, we propose: (1) identifying the specific phospho-Rab(s) mediating axonal phenotypes and aberrant phosphorylation of MAPs in neurons with LRRK2 G2019S, (2) assessing phospho-Rab and phospho-MAPs as possible biomarkers of target engagement for LRRK2 inhibitors in iPSCs-derived neurons, (3) validating the candidate biomarkers of LRRK2 target engagement using samples from patient cohorts, and (4) using iPSC-based models of idiopathic PD (iPD) stratified by common LRRK2 risk polymorphisms to determine if LRRK2 inhibitors could also be effective in subsets of iPD patients. Because we propose focusing on compounds that are being tested in phase I clinical trials, we argue that our proposal is poised to have a direct impact on the structure of clinical trials, which could lead to the first approved drug that effectively protects against PD pathogenesis.
DFG Programme
Research Grants
