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Magalhaes J, Tresse E, Ejlerskov P, et al. PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry. 2021;26(10):6083-6099doi: 10.1038/s41380-021-01207-w.
Magalhaes, J., Tresse, E., Ejlerskov, P., Hu, E., Liu, Y., Marin, A., Montalant, A., Satriano, L., Rundsten, C. F., Carlsen, E. M. M., Rydbirk, R., Sharifi-Zarchi, A., Andersen, J. B., Aznar, S., Brudek, T., Khodosevich, K., Prinz, M., Perrier, J. M., Sharma, M., Gasser, T., & Issazadeh-Navikas, S. (2021). PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Molecular psychiatry, 26(10), 6083-6099. https://doi.org/10.1038/s41380-021-01207-w
Magalhaes, Joana, et al. "PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia." Molecular psychiatry vol. 26,10 (2021): 6083-6099. doi: https://doi.org/10.1038/s41380-021-01207-w
Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, Montalant A, Satriano L, Rundsten CF, Carlsen EMM, Rydbirk R, Sharifi-Zarchi A, Andersen JB, Aznar S, Brudek T, Khodosevich K, Prinz M, Perrier JM, Sharma M, Gasser T, Issazadeh-Navikas S. PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry. 2021 Oct;26(10):6083-6099. doi: 10.1038/s41380-021-01207-w. Epub 2021 Jul 08. PMID: 34234281.
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Mol Psychiatry. 2021 Oct;26(10):6083-6099. doi: 10.1038/s41380-021-01207-w. Epub 2021 Jul 08.

PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia.

Molecular psychiatry

Joana Magalhaes, Emilie Tresse, Patrick Ejlerskov, Erling Hu, Yawei Liu, Andrea Marin, Alexia Montalant, Letizia Satriano, Carsten Friis Rundsten, Eva Maria Meier Carlsen, Rasmus Rydbirk, Ali Sharifi-Zarchi, Jesper Bøje Andersen, Susana Aznar, Tomasz Brudek, Konstantin Khodosevich, Marco Prinz, Jean-François Marie Perrier, Manu Sharma, Thomas Gasser, Shohreh Issazadeh-Navikas

Affiliations

  1. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  2. Neuronal Signaling Lab, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  3. Research Laboratory for Stereology and Neuroscience, Center for Translational Research, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark.
  4. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
  5. Institute of Neuropathology, Signalling Research Centres BIOSS and CIBSS, Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  6. Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  7. Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
  8. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. [email protected].

PMID: 34234281 DOI: 10.1038/s41380-021-01207-w

Abstract

Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb

© 2021. The Author(s).

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