Schlichte, R. | bioRxiv Science

bioRxiv2025

Protein kinase CK2 alpha prime as a dual modulator of immune signaling and synaptic dysfunction in Tauopathy

Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2 expression is elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2 levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2 depletion also attenuated microglial activation, pro-inflammatory cytokine production, and microglia synaptic engulfment, enhanced synaptic gene expression, synaptic density, and LTP. Importantly, CK2 depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways. One Sentence summaryThis study highlights CK2 as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling.

neuroscience↗

bioRxiv2024

Internalized α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade α-synuclein fibrils.

Parkinsons disease (PD) and other -synucleinopathies are characterized by the intracellular aggregates of -synuclein (S) believed to spread via the cell-to-cell transmission. To understand the contributions of various brain cells to the spreading of S pathology, we examined the metabolism of S aggregates in neuronal and glial cells. In neurons, while the full-length S rapidly disappeared following S PFF uptake, truncated S accumulated with a half-life of days rather than hours. Epitope mapping and fractionation studies indicate that S fibrils internalized by neurons was truncated at the C-terminal region and remained insoluble. In contrast, microglia and astrocytes rapidly metabolized S fibrils as the half-lives of S fibrils in these glial cells were <6 hours. Differential uptake and processing of S fibrils by neurons and glia was recapitulated in vivo where injection of fluorescently labeled S fibrils initially accumulated in glial cells followed by rapid clearance while neurons stably accumulated S fibrils at slower rate. Immunolocalization and subcellular fractionation studies show that internalized S PFF is initially localized to endosomes followed by lysosomes. The lysosome is largely responsible for the degradation of internalized S PFF as the inhibition of lysosomal function leads to the stabilization of S in all cell types. Significantly, S PFF causes lysosomal dysfunction in neurons. In summary, we show that neurons are inefficient in metabolizing internalized S aggregates, partially because S aggregates cause lysosomal dysfunction, potentially generating aggregation-prone truncated S. In contrast, glial cells may protect neurons from S aggregates by rapidly clearing S aggregates.

neuroscience↗