University of Georgia
Allosteric Targeting of LRRK2 in Parkinson's using Constrained Peptides
Parkinson's disease, PD, is a neurodegenerative disorder affecting more than five million people worldwide and only palliative treatment currently exists for the disease. Mutations in Leucine-rich repeat kinase 2, LRRK2, are the most frequent cause of late-onset and idiopathic PD. LRRK2 belongs to the group of Roco proteins, which are characterized by the presence of a Ras-like G-domain, Roc, a C-terminal of Roc domain, COR, a kinase and several protein-protein interaction domains. LRRK2 has a complex activation mechanism, involving intra-molecular signaling, dimerization and protein-protein interactions.
Significantly, several PD mutations in LRRK2 have been linked to decreased GTPase activity and increased kinase activity. However, it is not well understood how LRRK2 activity is regulated and how mutations in nearly every domain of the protein can alter the protein activity and function. Further, although mutations in LRRK2 are the most frequent cause of late-onset and idiopathic PD, each of the different but commonly occurring PD mutations in LRRK2 likely trigger different defects in LRRK2 function.
As a strategy to investigate LLRK2 regulation and function, we sought to develop hydrocarbon-constrained peptides to disrupt LRRK2 dimerization. These dimerization disruptors were found to be cell permeable and could significantly inhibit LRRK2 dimerization and kinase activity in cells. Further, unlike many LRRK2 kinase inhibitors, these allosteric compounds do not induce altered localization of LRRK2 in cells. Overall, the inhibitors may serve as an effective strategy to downregulate LRRK2 kinase function in cells and may also serve as templates for the development of therapeutic agents for PD.