Promising Outcomes of Original Grant:
We aimed at assessing the prion-like hypothesis of alpha-synuclein spread. Prions are small proteins that can move between cells, acting as infectious agents causing serious neurological disorders in animals and humans. According to our hypothesis, the Parkinson’s disease (PD)-associated protein alpha-synuclein could be released from donor cells, taken up by other cells and then cause clumping of the alpha-synuclein protein normally found in the recipient cells. Therefore, we transplanted dopaminergic nerve cells (the primary cell type affected in PD) from normal pre-clinical models into pre-clinical models that had been genetically modified to produce extra amounts of alpha-synuclein of the specific form found in humans. Six months after transplantion, we specifically detected such human alpha-synuclein within the transplanted pre-clinical cells, demonstrating that alpha-synuclein can move from cells into dopamine-producing nerve cells in living animals.
Objectives for Supplemental Investigation:
Despite the major significance of our findings, we found that the low rate of alpha-synuclein transfer in this model makes further analysis laborious and too time consuming for it to be a practical experimental tool. We believe that higher levels of alpha-synuclein in the host brain could favor alpha-synuclein transfer to the transplanted neurons. Thus, in the current proposal, we propose to apply the same thinking to a different pre-clinical model injected in the substantia nigra with virus that produces human alpha-synuclein. These pre-clinical models produce very high amounts of human alpha-synuclein in the part of the brain (called striatum) where we usually inject our transplants.
First, we will establish a precise time-course of alpha-synuclein transfer from the host brain to the grafted nerve cells. Then we will examine the ability of the transmitted human alpha-synuclein to promote protein clumping and characterize the putative alpha-synuclein inclusions induced in the transplanted nerve cells. We will also monitor the effects of alpha-synuclein transfer on the viability and function of the recipient neuron.
Importance of This Research for the Development of a New PD Therapy:
A prion-like mechanism of alpha-synuclein transfer may explain why the brain progressively degenerates in PD. Our project is likely to provide a robust pre-clinical model allowing investigation of the cellular mechanisms involved, which may lead to the development of novel disease-modifying therapies preventing the spreading of synuclein clumps in PD brains.