A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.

Background And Objectives: TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies.

The Ashkenazi-Centric G334R Variant of is Severely Impaired for Transactivation but Retains Tumor Suppressor Function in a Mouse Model.

Mutations in the tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis.

HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages.

Unlabelled: HIV establishes long-term latent infection in memory CD4 T cells and also establishes sustained long-term productive infection in macrophages, especially in the central nervous system (CNS). To better understand how HIV sustains infection in macrophages, we performed RNAseq analysis after infection of human monocyte-derived macrophages (MDMs) with the brain-derived HIV-1 strain YU2 and compared this with acute infection of CD4 T cells. HIV infection in MDM and CD4 T cells altered many gene transcripts, but with few overlaps between these different cell types.

Tip60's Novel RNA-Binding Function Modulates Alternative Splicing of Pre-mRNA Targets Implicated in Alzheimer's Disease.

The severity of Alzheimer's disease (AD) progression involves a complex interplay of genetics, age, and environmental factors orchestrated by histone acetyltransferase (HAT)-mediated neuroepigenetic mechanisms. While disruption of Tip60 HAT action in neural gene control is implicated in AD, alternative mechanisms underlying Tip60 function remain unexplored. Here, we report a novel RNA binding function for Tip60 in addition to its HAT function.

Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain.

Disruption of histone acetylation-mediated gene control is a critical step in Alzheimer's Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin (ChIP-seq) and transcriptional (RNA-seq) profiling study in brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes.

Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer's Disease.

Amyloid-β (Aβ) peptides can form protease-resistant aggregates within and outside of neurons. Accumulation of these aggregates is a hallmark of Alzheimer's disease (AD) neuropathology and contributes to devastating cognitive deficits associated with this disorder. The primary etiological factor for Aβ aggregation is either an increase in Aβ production or a decrease in its clearance.

Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown.

Hippocampal stimulation promotes intracellular Tip60 dynamics with concomitant genome reorganization and synaptic gene activation.

Genomic reorganizations mediating the engagement of target genes to transcription factories (TFs), characterized as specialized nuclear subcompartments enriched in hyperphosphorylated RNA polymerase II (RNAPII) and transcriptional regulators, act as an important layer of control in coordinating efficient gene transcription. However, their presence in hippocampal neurons and potential role in activity-dependent coregulation of genes within the brain remains unclear. Here, we investigate whether the well-characterized role for the histone acetyltransferase (HAT) Tip60 in mediating epigenetic control of inducible neuroplasticity genes involves TF associated chromatin reorganization in the hippocampus.

Sex differences in the effect of chronic mild stress on mouse prefrontal cortical BDNF levels: A role of major ovarian hormones.

Depression induced by stress is affected by sex, age and hormonal status of the animal and also by duration and type of the stressors. Moreover, higher prevalence of depression and comorbidities in women than men implies the need to include the sex variable in studies on animal models of depression. The present study was therefore initiated to evaluate the effect of sex and ovarian hormones on depression-like phenotypes in mice exposed to a 21-day Chronic Variable Mild Stress (CVMS) paradigm.

Sex difference in mouse hypothalamic transcriptome profile in stress-induced depression model.

The influence of sex on prevalence and presentation of human depression necessitates studying its role in depression. Additionally, stress can also affect the incidence and progression of depressive phenotypes. Hypothalamus is a well-reported sexually dimorphic brain region.

Differential effect of chronic stress on mouse hippocampal memory and affective behavior: Role of major ovarian hormones.

Molecular mechanisms of depression-like pathophysiology in female rodent models are less reported compared to males, despite its higher prevalence in human females. Moreover, the stress-response in brain circuitries including reward and cognition circuitries varies with age or hormonal status of the females. So, to understand the stress-induced mood and cognitive disorders in intact females (with ovaries) and ovariectomized (OVX) females, we studied changes in mouse hippocampus, a functionally heterogeneous neural structure involved in both affective and cognitive behaviors.