Study Rationale:
Induced pluripotent stem cells (iPSCs) have become widely used in the research community to investigate how mutations found in genetic studies of Parkinson’s disease (PD) alter the function of neurons and, ultimately, lead to disease. Technology allows cells harvested from blood samples of people with PD to be converted into iPSCs and then into neurons, which can then be used to study disease mechanisms. However, researchers typically produce these cell lines one at a time. We propose to generate a collection of cell lines, which will be available to the research community, in which we either introduce or correct PD-associated mutations.
Hypothesis:
We predict that we will be able to generate neurons, with or without PD mutations, and characterize them for use by the research community.
Study Design:
As part of the broader iPSC Neurodegenerative Disease Initiative (iNDI),we have identified an iPSC line that behaves predictably and for which we know the full genome sequence. We will use the CRISPR/Cas9 genome-editing technology to engineer into these cells a series of genetic mutations associated with inherited PD. In parallel, we will take cell lines that were previously produced from blood samples donated by participants in the Parkinson’s Progression Markers Initiative (PPMI) and remove the PD-associated mutations using the same approach. In both cases, we will establish methods for quality control that will ensure that the cells accrue no unexpected genetic alterations.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We hope to develop a community resource that will allow other laboratories to investigate the pathological changes caused by different PD mutations and to discover new ways to treat the disease.
Next Steps for Development:
Our major metric for success will be adoption of these cell lines by other laboratories. In the future, insights into the biology of PD may be derived by characterizing and comparing the changes seen in each of these cell lines.