Viruses need to keep cells alive during the course of their infection. We recently identified a novel viral RNA which does not code for any known protein but efficiently stops cells dying. This viral RNA interacts with an important component of the mitochondrion, protecting the cell from stress-induced death. We propose to ask whether this viral RNA can prevent neurodegeneration in models of Parkinson’s disease. This is a completely novel strategy using a non-immunogenic viral RNA to stabilize mitochondrial function – a function crucially important in the pathogenesis of PD.
Delivery of a neuroprotective RNA directly to cells or tissues is problematic because RNA, by itself, is rapidly degraded. However, complexing the RNA with a small peptide efficiently protects the RNA from this type of degradation. We will also engineer the peptide to make it able to cross the blood-brain barrier and specifically bind to neuronal cells. This will allow us to intravenously inject RNA/peptide complexes and deliver the viral RNA through the bloodstream to the central nervous system but it will also allow us to directly inject the peptide/RNA complex into the brain. Using these RNA/peptide complexes, we will test the ability of the novel viral RNA to prevent neurodegeneration and dopamine dysfunction in vivo, using established models of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The viral RNA we have already identified is used normally by the virus to help keep cells alive during the stress of virus infection. We have already shown that when it is delivered to neuronal cells, directly, it efficiently protects them from death signals and if delivered successfully to the brain could also work to prevent the type of neuronal cell death associated with PD from occurring. Anticipated Outcome:
Untimely cell death in the brain contributes to the pathology seen in PD. Any way of protecting neuronal cells from death may help to prevent the manifestations of the disease. Our work will determine if a novel viral RNA we have recently identified, which normally prevents cell death during virus infection, can act to prevent the type of neuronal cell death seen in PD and act a neuroprotective therapy.
Dr. Sinclair demonstrated that direct nigral injection of an RNA/peptide complex can protect against subsequent neurotoxicity in pre-clinical models, resulting in lessened behavioral deficits. The precise mechanism responsible for the protection conferred by the complex is not completely understood but likely involves protection of the mitochondria of neurons in the substantia nigra.