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

Overview

Authors: Erika B Villanueva1,2, Zala Zebec1, Marina Cisquella-Serra1, Jon Lundstrøm1, Jens V Andersen2, Filippa L Qvist2,3, Emil W Westi2, Andrea Marin1, Gisela Jimenez-Duran1, Lluís Riera-Ponsati1, Emilie Tresse1, Oliver Kretz4, Desiree Loreth5, Tobias Goldmann6, Thomas Blank6, Marco Prinz6,7,8,9, Blanca I Aldana2,9, Matthias Mann3, Niels H Skotte2,3, Shohreh Issazadeh-Navikas1
ORCID iDs: Erika B Villanueva, Jens V Andersen, Blanca I Aldana, Niels H Skotte
  1. Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, Neuroinflammation Unit, University of Copenhagen, Copenhagen Biocentre, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
  3. Faculty of Health and Medical Sciences, Novo Nordisk Foundation Centre for Protein Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
  4. Department of Internal Medicine III, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
  5. Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
  6. Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany
  7. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany
  8. Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany
  9. Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 15, 1870 Frederiksberg, Denmark
Institutions: University of Copenhagen (Denmark); Novo Nordisk Foundation (Denmark); University Medical Center Hamburg-Eppendorf (Germany); University of Freiburg (Germany)
Journal: Journal of biomedical science, volume 33, issue 1, article 57
Dates: received 21 August 2025; accepted 13 May 2026; published online 1 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s12929-026-01257-8 · PMID 42226039 · PMCID PMC13227799 · OpenAlex W7162991867
Open access: diamond, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), histology / microscopy (modality), human (organism), mouse (organism), Alzheimer's / dementia (population), Parkinson's (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Connectivity, Machine learning
Keywords: Parkinson’s disease dementia, IFNAR1, Mitochondria, Brain energy metabolism, SnRNA-seq, LC–MS/MS
MeSH: Astrocytes*, Brain*, Dementia*, Energy Metabolism*, Neurons*, Parkinson Disease*, Receptor, Interferon alpha-beta*, Animals, Humans, Male, Mice, Mice, Knockout (* major topic)
Topic: Parkinson's Disease Mechanisms and Treatments (Neurology, Medicine), according to OpenAlex
Funding: Lundbeck Foundation (R191-2015-1605, R223-2016-849); Danmarks Frie Forskningsfond (DFF-6110-00658); EU Horizon 2020 Research and Innovation Programme, Marie Sklodowska-Curie DISCOVER grant (10103491); Novo Nordisk Foundation BRIDGE Translational Excellence Programme (NNF20SA0064340)
Citations: not cited yet (Europe PMC); 108 references in the paper

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12929-026-01257-8.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Availability of data and materials

The snRNA-seq data has been deposited in the Gene Expression Omnibus (GEO) with the identifier GSE213671 [(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE213671) (https:/www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE213671)]. MS-based proteomics data is deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [108] with the identifier PXD037113 ([http://www.ebi.ac.uk/pride/archive/projects/PXD037113] (http:/www.ebi.ac.uk/pride/archive/projects/PXD037113)).

MS-based proteomics data is deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [108] with the identifier PXD037113 (http://www.ebi.ac.uk/pride/archive/projects/PXD037113).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 6 keywords, 12 MeSH terms, 4 funders, 106 references.

Cite

This paper

Villanueva, E. B., Zebec, Z., Cisquella-Serra, M., Lundstrøm, 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. (2026). Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia. Journal of biomedical science, 33(1), 57. https://doi.org/10.1186/s12929-026-01257-8

BibTeX

@article{villanueva2026distinct,
author = {Villanueva, Erika B and Zebec, Zala and Cisquella-Serra, Marina and Lundstrøm, Jon and Andersen, Jens V and Qvist, Filippa L and Westi, Emil W and Marin, Andrea and Jimenez-Duran, Gisela and Riera-Ponsati, Lluís and Tresse, Emilie and Kretz, Oliver and Loreth, Desiree and Goldmann, Tobias and Blank, Thomas and Prinz, Marco and Aldana, Blanca I and Mann, Matthias and Skotte, Niels H and Issazadeh-Navikas, Shohreh},
title = {{Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia}},
journal = {Journal of biomedical science},
year = {2026},
month = jun,
volume = {33},
number = {1},
pages = {57},
publisher = {BMC},
issn = {1021-7770},
doi = {10.1186/s12929-026-01257-8},
url = {https://doi.org/10.1186/s12929-026-01257-8},
pmid = {42226039},
pmcid = {PMC13227799}
}

RIS

TY - JOUR
AU - Villanueva, Erika B
AU - Zebec, Zala
AU - Cisquella-Serra, Marina
AU - Lundstrøm, Jon
AU - Andersen, Jens V
AU - Qvist, Filippa L
AU - Westi, Emil W
AU - Marin, Andrea
AU - Jimenez-Duran, Gisela
AU - Riera-Ponsati, Lluís
AU - Tresse, Emilie
AU - Kretz, Oliver
AU - Loreth, Desiree
AU - Goldmann, Tobias
AU - Blank, Thomas
AU - Prinz, Marco
AU - Aldana, Blanca I
AU - Mann, Matthias
AU - Skotte, Niels H
AU - Issazadeh-Navikas, Shohreh
TI - Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia
T2 - Journal of biomedical science
J2 - J Biomed Sci
PY - 2026
DA - 2026/06/01
VL - 33
IS - 1
SP - 57
SN - 1021-7770
PB - BMC
DO - 10.1186/s12929-026-01257-8
UR - https://doi.org/10.1186/s12929-026-01257-8
LA - en
ER -

CSL-JSON

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