Study Rationale:
The protein alpha-synuclein forms aggregates in the brains of people with Parkinson’s. Here, we will not look at the end stage of protein aggregation and cell death, which has been extensively studied. Instead, we will focus on the very earliest changes in cell biology and gene expression caused by exposure of healthy neurons, or brain cells, to native forms of alpha-synuclein secreted by neurons generated from people with Parkinson’s. Working with early time-points and patient alpha-synuclein will give the work dual relevance to disease and potential therapies.
Hypothesis:
Our hypothesis is that the earliest response to alpha-synuclein exposure may be the cause of cellular dysfunction and ultimately cell death.
Study Design:
We have previously generated stem cell lines from people with Parkinson’s and from healthy individuals. We have converted these stem cell lines into dopamine neurons, the type of brain cells that die in Parkinson’s, and shown that neurons from Parkinson’s patients secrete high levels of alpha-synuclein protein. Here we will grow dopamine neurons from Parkinson’s patients together in the same environment with neurons from healthy individuals. The healthy neurons will therefore be exposed to the high levels of alpha-synuclein protein released from the patient neurons. We will grow the neurons together for several weeks, harvest the cells, and look for the earliest changes in gene function in the healthy neurons.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our work will help us understand the very earliest response of a healthy dopamine neuron as it tries to cope with exposure to high levels of alpha-synuclein secreted by patient neurons. With this new information, we can then devise methods to help neurons respond and survive.
Next Steps for Development:
Our work will generate new targets, or points of therapeutic intervention, in neurons exposed to alpha-synuclein, which will enable us to develop new drugs for neuroprotective therapies to limit the damage in neurons caused by toxic forms of the protein.