Alpha-synuclein is a protein found in human neurons that can adopt a toxic form whose spread may be responsible for Parkinson’s disease. We showed that toxic alpha-synuclein is transported along the axons of neurons, from where it can be released and taken up by new neurons without the destruction of the first neurons. We propose to study the mechanisms of transport and transfer of the toxic protein to identify steps that could be targeted pharmacologically.
We will isolate neurons from pre-clinical models and culture them in devices called “microfluidic chambers”. These chambers will allow us to separate two groups of neurons which are connected only by their axons. We have developed the method of exposing one group of neurons to toxic alpha-synuclein and following both its transport through the axons and its delivery to the other group of neurons. We will use molecules known to block specific steps in transport and in known mechanisms cell-to-cell transfer of viruses and other pathogens, to identify the mechanisms used by toxic alpha-synuclein in its spread from neuron to neuron. The same experimental method can be used to screen potential drugs that would prevent spread of the toxic form of alpha-synuclein during Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
New mechanisms of transferring molecules between cells are being discovered, such as ‘unconventional secretion” and “tunneling nanotubes”. We will discover which of these is involved in the cell-to-cell spread of toxic alpha-synuclein and test the effect of inhibitors of this process on spread in neuronal cultures. Finding pharmaceutical agents that block, or even slow, the spread of toxic alpha-synuclein in the brain would be of great value in the treatment of the disease.
There are several ways by which proteins could be transported inside neurons and transferred from neuron to neuron. Our research will identify the ways involved in the case of toxic alpha-synuclein. It is possible that none of the known mechanisms is implicated in Parkinson disease and that we will discover some new pathways of transport and transfer. Eventually, we hope to learn how to block these mechanisms in human subjects.