Objective/Rationale:
LRRK2, a key protein in Parkinson’s disease, may have a role in regulating the cytoskeleton. The cytoskeleton in nerve cells (neurons) is crucial for the growth of neuronal processes, the transport along these processes and ultimately the communication between neurons crucial for normal brain function. Long neuronal projections affected in Parkinson's disease might be especially vulnerable in humans as a result of the size of the human neocortex. Therefore, defects in the interaction between LRRK2 and the cytoskeleton might lead to symptoms observed in people with Parkinson’s disease.
Project Description:
We have data suggesting that LRRK2 interacts with the cytoskeletal component tubulin and that LRRK2 mutations influence this interaction. This might lead to changes in cytoskeletal function with consequences for normal neuronal function as observed in Parkinson’s disease. First, we will investigate the LRRK2 tubulin interaction under basal conditions in a neuronal cell culture model mimicking neuronal development. Then we will determine whether LRRK2 mutations have an influence on cytoskeletal stability and therefore neuronal function in this model. We will observe changes at the tip of neuronal processes that are important for forming connections to other neurons. Thus we aim to determine whether LRRK2 influences dynamic cytoskeletal processes in health and disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Mutations in PARK8, encoding LRRK2 are a common known cause of familial Parkinson's disease. Since PARK8 mutations cause symptoms and signs similar to other forms of Parkinson’s disease, understanding the biological role of LRRK2 could help to uncover mechanisms contributing to disease progression. The interaction between LRRK2 and the cytoskeleton is one of several connections made between cytoskeletal dysfunction and Parkinson’s disease. Therefore, understanding how alterations in the LRRK2 cytoskeletal interaction contribute towards disease progression might identify some new disease modifying therapeutic targets.
Anticipated Outcome:
We expect to learn whether LRRK2 influences the stability of the tubulin cytoskeleton and cytoskeletal dynamics in neurons. In principle, mutations in LRRK2 leading to changes in cytoskeletal dynamics would affect neuronal heath. This might explain the reason why LRRK2 mutants can cause Parkinson’s disease. Thus this study will provide information about whether LRRK2 affects the cytoskeleton and therefore provide crucial information about the causes for cytoskeletal damage in Parkinson’s disease.