Targeting the LRRK2-PP2A complex in Parkinson’s disease – pLRRKInson

Neurodegenerative diseases represent a major public health issue that needs to be addressed. Among them, Parkinson's disease (PD) is considered as the most common motor pathology but for which no curative treatment is available. Recently, the gene coding for LRRK2 has emerged as one of the major genetic determinants of PD, both in familial and sporadic forms. In particular, several impacting mutations for LRRK2 kinase activity are correlated with the development of PD. Other works show a major role of LRRK2 phosphorylation in its biological function. Under physiological conditions, LRRK2 is highly phosphorylated and develops globally neuroprotective functions. In pathological conditions, LRRK2 phosphorylation is deregulated. The dephosphorylation of heterologous sites is initiated by protein phosphatases such as PP2A. Our goal is therefore to target the LRRK2/PP2A interaction in order to maintain the basal threshold of LRRK2 phosphorylation. We have identified peptides from PP2A that are ligands for LRRK2. We will study the binding interface between LRRK2 and these PP2A peptides to design optimized peptides as therapeutic tools/agents. We will also perform a high-throughput fluorescence polarization screening to identify small chemical modulators of the interaction. All of these new modulators will be evaluated in cellular models and may allow to validate a new therapeutic approach in PD.