Leucine-rich repeat kinase 2 (LRRK2) is mutated in rare forms of autosomal dominant (incomplete penetrance) Parkinson's disease (PD). There is still no disease-modifying treatment. Our understanding of PD pathogenesis is still poor. Despite major efforts, relatively little is known about the normal functions of LRRK2 (aside from it having GTPase and kinase domains) and what happens when it is mutated (beyond altered enzymatic activity).
The applicants propose that epidermal growth factor (EGF) can trigger LRRK2 activation.
In this revised application, an altered team proposes 3 aims for a 3-year project:
1) to explore the role of LRRK2 within a signaling cascade linking EGFR to synaptic vesicles
2) to examine the effects of pathological LRRK2 kinase activity on pre-synaptic functions
3) to study if drugs targeting EGFR-LRRK2 pathway can rescue pre-synaptic defects and deficits in neurotransmission induced by mutant LRRK2.
First, they plan to use biochemistry and cellular imaging to define the molecular interactions involved in the EGFR-LRRK2 pathway and their effects on pre-synaptic compartment. Second, they will study the effects of pathological LRRK2 mutations on synaptic vesicle function in cell- and animal-models, as well as purified synaptic vesicles. For example, they will examine the effects of LRRK2 mutations on both morphology and electrophysiological properties of primary neuronal cultures. They will use striatal synaptosomes and in vivo instrastriatal microdialysis to explore how dopamine release is affected by mutant LRRK2 and knocking out LRRK2 in mice. Third, they will study possible therapeutic effects of drugs that target the EGFR-LRRK2 pathway in LRRK2 experimental models. For example, they will assess the effects of different LRRK2 inhibitors combined with modulators of the EGF-pathway on the synaptic defects (studied above), as well as on motor behaviour in mice that either have LRRK2 mutations or that are null mutant for LRRK2.
