Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegeneration. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, synthesis, and energy production. Concomitantly, Alzheimer’s disease (AD) case subjects show increased nucleolin and a decrease in SIRT6 levels. AD case subjects present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD case subjects is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation, and nucleolar dysfunction.X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. selleck Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum.The γ-chain receptor dimerizes with complexes of the cytokines interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 and their corresponding “private” receptors. These cytokines have existing uses and future potential as immune therapies because of their ability to regulate the abundance and function of specific immune cell populations. Here, we build a binding reaction model for the ligand-receptor interactions of common γ-chain cytokines, which includes receptor trafficking dynamics, enabling quantitative predictions of cell-type-specific response to natural and engineered cytokines. We then show that tensor factorization is a powerful tool to visualize changes in the input-output behavior of the family across time, cell types, ligands, and concentrations. These results present a more accurate model of ligand response validated across a panel of immune cell types as well as a general approach for generating interpretable guidelines for manipulation of cell-type-specific targeting of engineered ligands.Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke. In vivo two-photon imaging provides evidence of astrocytes contacting newly formed vessels in cortex surrounding photothrombotic infarcts. Chemogenetic ablation of a subset of reactive astrocytes after stroke dramatically impairs vascular and extracellular matrix remodeling. This disruption of vascular repair is accompanied by prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. In contrast, vascular structure in the non-ischemic brain is unaffected by focal astrocyte ablation. These findings position reactive astrocytes as critical cellular mediators of functionally important vascular remodeling during neural repair.