Study Rationale: Our previous work shows that regulation of the phosphorylation of the Parkinson’s disease protein ‘leucine-rich repeat kinase 2’ (LRRK2) is a key mechanism controlling LRRK2 activation. Also, since LRRK2 phosphorylation is lowered in disease, we are proposing here a novel approach to target LRRK2 pathological activity by inhibiting the reduction of LRRK2 phosphorylation at specific sites (Ser910/935). We have discovered potent and specific molecules that stabilize a protein that protects LRRK2 phosphorylation, called 14-3-3 proteins. For this project, we will further develop these novel LRRK2 phosphorylation stabilizing compounds and expand our testing to reduce LRRK2 activity and pathophysiological phenotypes in cells and animal models.
Hypothesis: 14-3-3 proteins are known to bind phosphorylated Ser910/Ser935 acting as a cap that prevents LRRK2 dephosphorylation. Stabilizing the LRRK2:14-3-3 interaction will therefore favor the phosphorylated form of LRRK2 and avoid accumulation of the disease associated dephosphorylated form.
Study Design: On the one hand, we will develop the chemistry of our compounds based on the most potent and selective LRRK2:14-3-3 stabilizing tool compounds that we have identified from our collection. On the other hand, we will test these compounds in an expanded testing pipeline to confirm that the most promising compounds can indeed block LRRK2 activity and functioning in molecular and cellular models. We will then determine whether administration of these compound can block the PD-related phenotypes in models of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our novel LRRK2:14-3-3 stabilizing compounds will represent both an alternative LRRK2 targeting strategy in its own right as well as a targeting strategy potentially complementing LRRK2 kinase inhibition. As a disease-modifying agent, the therapeutic is predicted to be active at all stages of the disease.
Next Steps for Development: Prior to proceeding to a follow up study, we wish to have at the end of the project at least 1 compound that is brain penetrant, that effectively stabilizes LRRK2 binding to 14-3-3 in cells and that reverts pathophysiological phenotypes in chronic cellular models. This will set the stage for ongoing long-term studies in pre-clinical in vivo models.