Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia

Abstract Background Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson’s disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Methods Single nuclei RNA sequencing (snRNA-seq), liquid chromatography tandem mass spectrometry (LC–MS/MS), functional metabolic mapping, flow cytometry, quantitative PCR (qPCR), in situ hybridization, immunofluorescence and immunohistochemistry, Western blotting, and behavior analyses were used to investigate the molecular, cellular, and phenotypic impacts of IFNAR1 loss in vivo . Results Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls. Neuron- and astrocyte-specific transcriptomic and proteomic alterations in Ifnar1 –/– mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, Ifnar1 –/– mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1. Conclusions IFNAR1 plays a crucial role in brain and mitochondrial homeostasis, loss of which results in neurodegeneration and neuropathology resembling PDD. Differential neuropathology and behavioral outcomes upon neuronal vs astrocytic IFNAR1 loss emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. Trial registration Not applicable as the study does not include a clinical trial.