Study Rationale:
Deposits of the alpha-synuclein protein are the key cellular pathology recognized to drive the progression of Parkinson’s disease leading to the death of neurons. The alpha-synuclein aggregates are likely a late-stage marker of cell dysfunction and very little is known about the early impact of exposure of cells to alpha-synuclein and the impact that may have on gene expression. Our laboratory works on patient stem cells and stem cell-derived neurons to study Parkinson’s. In our previous work we found that Parkinson’s stem cell-derived neurons release alpha-synuclein. Here we will investigate the effect this alpha-synuclein has on healthy neurons grown alongside the Parkinson’s neurons.
Hypothesis:
Here, in this work, we will expose healthy stem cell-derived neurons to alpha-synuclein produced from Parkinson’s neurons and investigate the impact of the alpha-synuclein on gene expression in the recipient cells. This use of patient-derived alpha-synuclein is a refined physiological model of disease we have developed. Early changes in gene expression induced by the alpha-synuclein in otherwise healthy neurons may represent some of the first things that may go wrong as disease sets in, and may therefore represent processes which can be targeted by therapies.
Study Design:
First, we will grow the Parkinson’s neurons alongside the healthy neurons and watch the transfer of human alpha-synuclein from the Parkinson’s neurons to the healthy neurons. We will then harvest the healthy neurons which have been exposed to patient alpha-synuclein and perform gene expression analysis on individual cells to obtain with a high level of accuracy information on the perturbation of gene expression caused by the disease protein. Finally, we will compare findings from our more physiological model to results from a more aggressive and widely-used model of cellular alpha-synuclein cellular pathology using artificial pre-formed protein aggregates.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The mechanistic insight gained will address specific early changes in alpha-synuclein biology which may represent new and improved targets for neuroprotective therapy.
Next Steps for Development:
Once the early changes in cellular pathways have been identified, our group and others can identify potential drug targets within the altered processes which could then be used to design novel therapies.