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Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy.

Overview

Authors: Angel White1, Peter Gavrilyuk1, Persephone Gu1, Rafael Falcon-Moya1, Reid Thurston1, Amal Fickak1, Nicholas B. Rozema1, Prarthana Keshavaram1, Scott Vermilyea1, Riley Schlichte1, Joyce Meints1, Ying Zhang2, Alfonso Araque1, Michael K. Lee1, Rocio Gomez-Pastor1
  1. School of Medicine, Department of Neuroscience, University of Minnesota,Minneapolis, MN USA
  2. Minnesota Supercomputing Institute, University of Minnesota,Minneapolis, MN USA
Institutions: University of Minnesota (United States)
Journal: Translational neurodegeneration, volume 15, issue 1, article 31
Dates: received 27 January 2026; accepted 27 May 2026; published online 9 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s40035-026-00563-3 · PMID 42426923 · PMCID PMC13348822 · OpenAlex W4413036389
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.21203/rs.3.rs-7078069/v1
Status: data only
Categories: histology / microscopy (modality), human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, fMRI & imaging
Keywords: Tauopathy, CK2, CK2α′, Microglia, Phagocytosis, Synaptic function
MeSH: Casein Kinase II*, Neuroimmunomodulation*, Signal Transduction*, Synapses*, Tauopathies*, Animals, Brain, Female, Humans, Male, Mice, Mice, Transgenic, Neurons, tau Proteins (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: NIH (R01MH119355, R01AG077743, R01NS110694); DOD (W911NF2110328)
Citations: not cited yet (Europe PMC); 119 references in the paper
Research resources: mouse anti-PHF1 RRID:AB_2315150, RRID:SCR_011323

Abstract

Background: Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein kinase CK2 is a holoenzyme composed of two regulatory (CK2β) and two catalytic subunits (CK2α and CK2α′) and has been linked to multiple aspects of tau pathology. However, genetic evidence defining the specific contributions of CK2 subunits to tau phosphorylation and tauopathy remains lacking. Elucidating subunit-specific roles is critical for the rational development of CK2-targeted therapies.

Methods: To investigate the impact of CK2 in tauopathy, Neuro-2a and primary cell cultures expressing mutant tau were treated with siRNAs targeting the two catalytic subunits of CK2, CK2α and CK2α′. In addition, the PS19 mouse model of tauopathy was bred to be haploinsufficient for the catalytic subunit CK2α′. Changes in pathology and symptomatology were analyzed via immunohistochemistry, immunoblotting, RNA-sequencing, in situ hybridization, electrophysiology, and Barnes Maze.

Results: We found that the expression of the catalytic subunit CK2α′, but not catalytic CK2α or regulatory CK2β subunits, was elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using a haploinsufficient model of CK2α′ in PS19 mice, we demonstrated that the PS19:CK2α′(+/−) mice had significantly decreased phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α′ depletion also attenuated microglial activation, pro-inflammatory cytokine production and microglia synaptic engulfment, and enhanced synaptic gene expression, synaptic density, and long-term potentiation. Importantly, CK2α′ haploinsufficiency rescued cognitive deficits assessed in the Barnes maze.

Conclusions: Here, we show CK2α′, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α′-dependent modulation of tau phosphorylation as well as neuroinflammatory and immune signaling pathways. These findings identify CK2α′ as a mechanistically defined and potentially druggable target for therapeutic strategies aimed at modifying tau-driven neurodegeneration.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40035-026-00563-3.

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

Code

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Data

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Availability of data and materials

RNA-Seq data generated in this study are available in the Gene Expression Omnibus repository found at https://www.ncbi.nlm.nih.gov/geo/ with accession number GSE298505. The reviewer token to access the GEO deposited data is mlwxmuactlibryl. Allan Brain Atlas Aging, Dementia and TBI dataset that supports conclusions of this article is publicly available at https://aging.brain-map.org/overview/home [60]. Human brain tissue was received from the NIH NeuroBioBank repository and is available publicly for request at https://neurobiobank.nih.gov/. scRNA-Seq study data from human samples that contributed to conclusions of this article can be found in The Alzheimer's Cell Atlas (TACA) https://taca.lerner.ccf.org/ [67–71].

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, 15 authors, 6 keywords, 14 MeSH terms, 2 funders, 119 references, 2 RRIDs.

Cite

This paper

White, A., Gavrilyuk, P., Gu, P., Falcon-Moya, R., Thurston, R., Fickak, A., Rozema, N. B., Keshavaram, P., Vermilyea, S., Schlichte, R., Meints, J., Zhang, Y., Araque, A., Lee, M. K., & Gomez-Pastor, R. (2026). Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy. Translational neurodegeneration, 15(1), 31. https://doi.org/10.1186/s40035-026-00563-3

BibTeX

@article{white2026protein,
author = {White, Angel and Gavrilyuk, Peter and Gu, Persephone and Falcon-Moya, Rafael and Thurston, Reid and Fickak, Amal and Rozema, Nicholas B. and Keshavaram, Prarthana and Vermilyea, Scott and Schlichte, Riley and Meints, Joyce and Zhang, Ying and Araque, Alfonso and Lee, Michael K. and Gomez-Pastor, Rocio},
title = {{Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy}},
journal = {Translational neurodegeneration},
year = {2026},
month = jul,
volume = {15},
number = {1},
pages = {31},
publisher = {BMC},
issn = {2047-9158},
doi = {10.1186/s40035-026-00563-3},
url = {https://doi.org/10.1186/s40035-026-00563-3},
pmid = {42426923},
pmcid = {PMC13348822}
}

RIS

TY - JOUR
AU - White, Angel
AU - Gavrilyuk, Peter
AU - Gu, Persephone
AU - Falcon-Moya, Rafael
AU - Thurston, Reid
AU - Fickak, Amal
AU - Rozema, Nicholas B.
AU - Keshavaram, Prarthana
AU - Vermilyea, Scott
AU - Schlichte, Riley
AU - Meints, Joyce
AU - Zhang, Ying
AU - Araque, Alfonso
AU - Lee, Michael K.
AU - Gomez-Pastor, Rocio
TI - Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy
T2 - Translational neurodegeneration
J2 - Transl Neurodegener
PY - 2026
DA - 2026/07/09
VL - 15
IS - 1
SP - 31
SN - 2047-9158
PB - BMC
DO - 10.1186/s40035-026-00563-3
UR - https://doi.org/10.1186/s40035-026-00563-3
LA - en
ER -

CSL-JSON

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