Biology subjects

Parylak, S. L.

Publications and source records attributed to Parylak, S. L..

3 recordsLinked to original sources

bioRxiv2025

CK2 inhibition suppresses glial inflammation in the brain

Neuroinflammation plays a key role in Alzheimers disease (AD) and related neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis. However, glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK22, as a key driver of astrocytic inflammation. CK2 enhances NF-{kappa}B activity by phosphorylating NF-{kappa}B S529 and I{kappa}B S32, promoting pro-inflammatory gene expression. CK2 inhibition via genetic or chemical approaches dampens inflammation, including IL-6 and IL-8 expression in an acute neuroinflammation mouse model. CK22 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK22 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in transgenic AD mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders.

neuroscience↗

bioRxiv2022

Neuronal activity-related transcription is blunted in immature compared to mature dentate granule cells

Immature dentate granule cells (DGCs) generated in the hippocampus during adulthood are believed to play a unique role in dentate gyrus function. Although immature DGCs have hyperexcitable membrane properties in vitro, the consequences of this hyperexcitability in vivo remain unclear. In particular, the relationship between experiences that activate the dentate gyrus, such as exploration of a novel environment (NE), and downstream molecular processes that modify dentate gyrus circuitry in response to cellular activation are unknown in this cell population. We first performed quantification of immediate early gene proteins in immature (5-week-old) and mature (13-week-old) DGCs from mice exposed to a NE. Paradoxically, we observed lower immediate early gene protein expression in hyperexcitable immature DGCs. We then isolated nuclei from active and inactive immature DGCs and performed single nuclei RNA-Sequencing. Compared to mature nuclei collected from the same animal, immature DGC nuclei showed less activity-induced transcriptional change, even though they were classified as active based on expression of ARC protein. These results demonstrate that the coupling of spatial exploration, cellular activation, and transcriptional change differs between immature and mature DGCs, with blunted activity-induced changes in immature cells.

neuroscience↗

bioRxiv2020

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hours post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentate gyrus (DG)--without ablating adult neurogenesis--can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo 2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system (CNS) should be carefully evaluated.

neuroscience↗