Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration

Brain expression of AAV-Ifn-gamma leads to reactive gliosis, nigrostriatal degeneration and midbrain calcification in wild type mice. This mouse model phenocopies idiopathic basal ganglia calcification which is associated with Parkinsonian symptoms. To understand how the nigro-striatal pathway is selectively vulnerable to Ifn-gamma, we determined if the phenotype is driven by canonical signaling intermediates, Ifngr1 and Stat1. Using focused bioinformatic analysis and rotarod testing, we show that neuroinflammation and motor abnormalities precede the appearance of midbrain neuropathologies in the brains of Ifn-gamma mouse model. To test whether canonical Ifn-gamma signaling is a key driver of progressive nigrostriatal degeneration, we overexpressed Ifn-gamma in the brains of Ifngr1(-/-) and Stat1(-/-) mice. Expression of Ifn-gamma in Ifngr1(-/-) mice did not result in any neuroinflammation, midbrain calcinosis or nigrostriatal degenerative pathology. Interestingly, in Stat1(-/-) mice, Ifn-gamma expression resulted in gliosis without recapitulating the neurodegenerative phenotype. Overall, our data shows that canonical Ifn-gamma signaling triggers midbrain calcinosis and nigrostriatal neurodegeneration, providing mechanistic insights into cytokine-driven selective neuronal vulnerability. Our study establishes the broader relevance of inflammatory signaling in neurodegenerative diseases and can potentially identify novel immunological targets for Parkinsonian syndromes.