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