Objective/Rationale:
Over-activation of immune cells in the brain can lead to increased neuron loss in diseases such as Parkinson’s. Fractalkine is a protein that is a key player in controlling inflammation and can reduce an inflammatory response. We are therefore studying the potential benefits of fractalkine in reducing neuron loss in the alpha-synuclein animal model.
Project Description:
To examine the beneficial effects of fractalkine we will use gene delivery via a viral vector to overexpress fractalkine in neuronal cells of pre-clinical models. We will also examine the effects of increased expression of fractalkine in other non-neuron brain cells (astrocytes) as this may yield distinct differences from neuronal expression due to a) different positioning and/or functional association of astrocytes with microglia (immune cells) and b) different expression of fractalkine processing proteases that might be found in astrocytes but not in neurons. Further astrocyte expression may be a better target in Parkinson’s patients where significant neuron loss/dysfunction has already occurred. The pre-clinical model we will use to test for protection of neuron loss will have overexpression of the human alpha-synuclein protein, which forms Lewy bodies in Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will hopefully identify fractalkine as a therapeutic target for treatment of Parkinson’s disease. Our hypothesis is that increased expression of fractalkine will lead to neuronal protection of dopaminergic neurons by reducing pro-inflammatory responses in Parkinson’s pre-clinical models. This could lead to the design of drugs that have the potential to mimic the same neuron protection in Parkinson’s patients.
Anticipated Outcome:
We believe this proposal will lead to the identification of fractalkine as a therapeutic target for Parkinson’s disease. In particular, suggesting that fractalkine receptor activators would offer therapeutic potential for synuclein related dopamine neuron loss. Further, this study could potentially identify enzymes that cleave fractalkine as targets for drug intervention. Alternatively, this proposal may imply a gene therapeutic intervention for dopamine neuron loss using one or more of the fractalkine viral constructs in this proposal.
Progress Report
We have completed our preliminary studies with the use of viral vectors and the MPTP pre-clinical model. As our timeline indicates we have generated all viral vectors to be used for this study. We have shown successfully that these vectors work in vivo and are ready for study use. Models described in Aim 1 have been injected with the viral particles and behavioral analysis was performed after one month of treatment. The models were euthanized and their brains are currently being examined for pathology development. In Aim 2 we have generated the viruses required and tested them in vivo. These viruses are expressing the proteins we are studying and there will be used to inject the models for aim 2.