Validation of an early interferon signaling response in the dopamine-denervated striatum in a mouse model of Parkinson’s disease

Parkinson's disease is characterized by the progressive loss of striatal dopaminergic innervation and widespread neuroinflammation. Although levodopa (L-DOPA) is the gold standard symptomatic therapy, chronic use generates adverse effects known as L-DOPA-induced dyskinesias (LID). Understanding the cellular adaptations of the striatal network during dopamine depletion and LID, is therefore critical for translational medicine. Using single-nucleus RNA sequencing of striata from intact and hemiparkinsonian mice, we characterized cell-type-specific transcriptional profiles at 5 and 28 days after 6-OHDA-induced dopaminergic denervation. We identified an early inflammatory response characterized by increased expression of interferon (IFN)-related genes across most striatal cell types, including a subset of IFN-responsive microglia. The aims of the project will be to validate the presence of the inflammatory microenvironment in an independent cohort by combining RT-qPCR and confocal immunofluorescence targeting the IFN/JAK/STAT pathway. We will then pharmacologically inhibit this pathway using an FDA-approved drug and assess its effect on neuroinflammation, dopaminergic cell loss and motor function. Finally, we will investigate whether IFN-mediated response contributes to maladaptive circuit changes and susceptibility to LID. Identifying these mechanisms may reveal therapeutic targets to protect striatal circuits and reduce dyskinesias while preserving the motor benefits of L-DOPA