We have preliminary evidence that LRRK2, which is a key protein in Parkinson’s disease (PD), may have a role in an important cellular process called Wnt signaling. Thus it is possible that LRRK2 mutations that have been found to cause PD may do so by altering this process of Wnt signaling. As a key step towards investigating Wnt signaling in PD, we will investigate whether LRRK2 has a role in Wnt signaling in pre-clinical models.
We have preliminary data suggesting that LRRK2 plays a role in a process called Wnt signaling. If so, LRRK2 mutations may lead to failures in Wnt signaling, which could contribute to PD. Thus, we will investigate whether LRRK2 and a central Wnt signaling protein called Disheveled physically interact within the neurons of the pre-clinical model. We will also determine whether the amount of LRRK2 present within the pre-clinical model can influence the activity of Wnt signaling. In parallel, we will perform experiments using cultured cells to determine whether two PD-causing LRRK2 mutations may affect Wnt signaling. Thus we aim to determine whether LRRK2 influences Wnt signaling in the pre-clinical model, and whether mutations to LRRK2 might affect this process, thereby leading to PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 is not the only protein associated with PD that has also been linked to Wnt signaling. It is quite possible therefore, that impairments in Wnt signaling are a major event contributing towards this disease. Wnt signaling is a process that is potentially very amenable to drug targeting. In the long-term therefore, it is quite possible that this work could lead the way to a number of possible treatments.
We expect to learn whether LRRK2 may function in Wnt signaling in pre-clinical models. In principle, impaired Wnt signaling could explain much about Parkinson’s disease, so this idea is exciting. However our data comes from cell lines, and not all observations from cell lines hold true for humans and pre-clinical models. Thus this study will provide critical information about whether LRRK2 affects Wnt signaling in pre-clinical models and whether this is likely to be relevant to PD.