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bioRxiv · 10.1101/2025.08.14.670043

Distinct and Combined Interferon-α/β-receptor-1 Loss in Neurons and Astrocytes Disrupt Brain Energy Metabolism and Drive Parkinsonian Dementia

Villanueva, E. B.·Zebec, Z.·Lundstrom, J.·Andersen, J. V.·Qvist, F. L.·Westi, E. W.·Marin, A.·Jimenez-Duran, G.·Riera-Ponsati, L.·Tresse, E.·Kretz, O.·Loreth, D.·Goldmann, T.·Blank, T.·Prinz, M.·Aldana, B. I.·Mann, M.·Skotte, N. H.·Issazadeh-Navikas, S.
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Abstract

Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinsons 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. Here it is shown that baseline IFNAR1 expression varies in the 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 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 specifically recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1. This work supports a crucial role of IFNAR1 in brain homeostasis and emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. HighlightsO_LIIFNAR1 and related type-I IFN genes are differentially expressed among major brain cell types in Parkinsons Disease, Lewy Body Dementia, and unaffected controls C_LIO_LIEarly molecular alterations in Ifnar1-/- mice show lack of immunomodulation contributing to neuroinflammation, mitochondrial defects, and dysregulated energy metabolism C_LIO_LIIfnar1-/- mice develop a progressive Parkinsonian-like disease phenotype, including dopaminergic cell loss in substantia nigra, cortical neurodegeneration, phosphorylated (p)alpha-synuclein+ and pTau+ Lewy-body-like inclusions, neuroinflammation, and progressive motor, cognitive, and neuropsychiatric disturbance-like behavior deficits C_LIO_LINeuropathologies, motor, and cognitive deficits are recapitulated in mice lacking neuronal IFNAR1 (Syn1Cre;Ifnar1fl/fl) whereas neuropsychiatric abnormalities are recapitulated in mice lacking astrocytic IFNAR1 (GFAPCre;Ifnar1fl/fl) C_LI

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Villanueva, E. B., Zebec, Z., Lundstrom, J., Andersen, J. V., Qvist, F. L., Westi, E. W., Marin, A., Jimenez-Duran, G., Riera-Ponsati, L., Tresse, E., Kretz, O., Loreth, D., Goldmann, T., Blank, T., Prinz, M., Aldana, B. I., Mann, M., Skotte, N. H., Issazadeh-Navikas, S.. 2025-08-19. Distinct and Combined Interferon-α/β-receptor-1 Loss in Neurons and Astrocytes Disrupt Brain Energy Metabolism and Drive Parkinsonian Dementia. https://doi.org/10.1101/2025.08.14.670043

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