Several lines of research suggest that leucine-rich repeat kinase 2 (LRRK2 or PARK8) levels or its activity can regulate the development of axons or dendrites, but some of the data are conflicting, and it is not clear where and how LRRK2 acts during the course of neuron development. In this project, we will determine the impact of LRRK2 levels and LRRK2 activity on the generation of axons, the elaboration of dendrites and the development of synapses.
Recently developed pre-clinical bacterial artificial chromosome (BAC) transgenic models have provided the field with tools that can be used to systematically investigate roles for LRRK2 during neuronal differentiation. These pre-clinical models express LRRK2, LRRK2 G2019S, or a LRRK2 kinase dead mutant in a cell type specific manner that closely resembles native LRRK2 expression. Native LRRK2 is expressed throughout hippocampus, and hippocampal neurons grown in culture have served as an excellent model system in which to evaluate neural differentiation. The pre-clinical and culture model systems together will permit us to determine definitively the role that LRRK2 plays in neural differentiation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Mutations in the gene encoding LRRK2 have been linked to the most common forms of familial Parkinson's disease. The most prevalent disease causing mutations increase
LRRK2 kinase activity suggesting that therapies designed to reduce activity may be relevant for treating PD, but in the absence of known, readily measured biological outcomes, it is not yet possible to design high throughput analyses to screen candidate reagents. Axon and dendrite outgrowth are readily measured outcomes that can be used to screen candidate proteins.
The experiments will determine precisely how LRRK2 regulates neural differentiation. The outcomes will allow us to better understand LRRK2 function as well as to establish bioassays for drug screening.