The goal of this CIRM early translational grant is to develop a model for “Parkinson’s disease (PD) in a culture dish” using patient-specific induced pluripotent stem cell lines (iPS). The underlying idea is to utilize these lines as an experimental pre-clinical model to study disease mechanisms unique to PD that could lay the foundation for drug discovery.
Over the last year, we have expanded our patient skin cell bank to 57 cell lines and the iPS cell bank to 39 well-characterized pluripotent stem cell lines from PD patients and healthy controls individuals. We have improved current protocols of neuronal differentiation from patient-derived iPS lines into dopamine producing neurons and can show consistency and reproducibility of making midbrain dopamine expressing nerve cells.
In our first publication (Nguyen et al. 2011), we describe for the first time differences in iPS-derived neurons from a PD patient with a common causative mutation in the LRRK2 gene. These patient cells are more susceptible for cellular toxins leading ultimately to more cell degeneration and cell death.
We are also investigating a common disease mechanism implicated in PD, which is mitochondrial dysfunction. In skin cells of a patient we were able to find profound deficits of mitochondrial function compared to control lines and we are now in the process of confirming these results in neural precursors and mature dopamine neurons.
Overall, we have made substantial progress towards the goal of this grant which is the a new cell culture model of PD which can replicate PD-related cellular pathology.