Progetto LRRK2-PAK6

  • Characterization of LRRK2-PAK6 signaling pathway

In a previously funded project, we used a high-throughput protein interaction screens and identified novel biological pathways for LRRK2 as well as for its closest homolog LRRK1 not linked to Parkinson’s disease.

In this supplemental project we plan to specifically focus on the interaction between p21-activated kinase 6 (PAK6) and LRRK2. In the nervous system, finely controlled neuronal network is fundamental for maintenance of brain architecture and cognitive functions. Dynamic changes in actin cytoskeleton provide the mechanical force for neurite outgrowth and synapse formation, and defective cytoskeleton dynamics have been linked to multiple neurodegenerative diseases. In our previous award, we demonstrated that PAK6 links LRRK2 to actin cytoskeleton and that kinase activity of class II PAKs (PAK4-6) is a negative regulator of LRRK2 phosphorylation state. Our current aim is to understand the functional role of LRRK2-PAK6 complex on neuronal morphogenetic processes linked to actin dynamics using established in vitro and in vivo assays.

To date, a number of selective and potent LRRK2 inhibitors have been developed but it remains unclear whether inhibition of LRRK2 activity protects against neuronal death. Remarkably, pharmacological inhibition of LRRK2 results in protein dephosphorylation and relocalization similarly to what observed in cells overexpressing the majority of LRRK2 mutations and in brains from knock-in R1441C mice. Our results clearly demonstrated that kinase activity of class II PAKs induces LRRK2 dephosphorylation and relocalization, suggesting that inhibition of these kinases may represent a novel pharmacological approach alternative to direct LRRK2 inhibition.

Principal Investigators