Past observations in LRRK2 pre-clinical models have lead us to develop a unified hypothesis for LRRK2’s role in signaling/scaffolding and neuronal membrane dynamics. By utilizing ex vivo and in vivo approaches we will answer fundamental questions relevant to normal LRRK2 function and its contribution to PD pathogenesis. Most work will be performed using LRRK2 knock-out mice to see whether LRRK2 wild-type or mutant fragments, or Lrrk1, can rescue growth defects observed.
The majority of ex vivo experiments will be done in tissue culture, quantifying neuronal membrane growth. Focused on neuronal arborization in cells derived from murine LRRK2 knock-out mice (mKO) we will explore the role of wildtype and mutant LRRK2, as well as its independent functional domains. We will also test whether Lrrk1 expression can compensate for LRRK2 loss. Work in vivo we will focus on pre-synaptic dopamine release and post-synaptic spine maintenance in mKO animals. These phenotypes appear to be directly related through LRRK2’s function in secretory pathway trafficking and membrane dynamics.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Results from the studies proposed are likely to have benefit in both LRRK2-parkinsonism and idiopathic Parkinson’s disease. It is now widely recognized that pathogenic mutations in LRRK2 greatly increase the risk of parkinsonism within carriers. Conversely, normal LRRK2 function appears to be required for successful aging of the basal ganglia. Although the experiments planned will inform basic LRRK2 functional biology, the results will directly contribute to the development of cell-based and in vivo assays providing a simple read-out of efficacy for future compound screening. systems Robust ‘etiologic’ are vital for, to develop novel therapeutics aimed at neuroprotective and Symptoms & Side Effects therapies.
Experiments are likely to provide insight in basic mechanism of Lrrk biology, including the role of specific domains and mutations implicated in Parkinson’s disease. It is likely the findings will directly inform the development of functional assays that might be exploited to identify and develop novel treatments. As the scientific approach is based on a mechanistic and molecular understanding of disease etiology, downstream therapeutics are more likely to be efficacious.