Neuroscience Bulletin

Glioma is the most common primary malignant tumor of the brain, and accumulating evidence indicates that neuronal activity plays a pivotal role in tumor progression. In this study, neuronal activity is modulated in vitro using potassium chloride (KCl)-induced depolarization and midazolam (MDZ)-mediated suppression. MDZ is a neuronal activity modulation medication, commonly used for sedation, anxiolysis, and amnesia in clinics. After treatment, conditioned media derived from these neuronal cultures are subsequently co-cultured with glioma cells. EdU incorporation assays demonstrate that MDZ significantly inhibits glioma cell proliferation in vitro. Furthermore, an orthotopic xenograft glioma model is established to assess the anti-tumor efficacy of MDZ in vivo, as evaluated by tumor volume and Ki-67 immunostaining. Mechanistically, insulin-like growth factor 1 (IGF1) is identified as the neuronal-activity-regulated factor that promotes glioma growth through activation of the PI3K/AKT signaling pathway. Moreover, transcriptomic profiling of brain tissues reveals that MDZ attenuates neuronal activity and downregulates neuron-derived growth factors in both glioma and non-tumor regions, thereby exerting anti-tumor effects in vivo. Collectively, these findings demonstrate that MDZ suppresses glioma progression by suppressing neuronal activity and inhibiting neuron-derived trophic factors, providing new insights into the development of therapeutic strategies for glioma.

Alzheimers disease (AD), the leading cause of dementia, affects over 33 million people worldwide, with pathogenesis tied to amyloid-{beta} (A{beta}) accumulation. Although anti-A{beta} monoclonal antibodies have shown clinical benefits, they often cause side effects including amyloid-related imaging abnormalities and brain microhemorrhage, especially in APOE E4 allele carriers. Here we used PHP.eB serotype adeno-associated virus (AAV), a vector with enhanced central nervous system (CNS) tropism, to deliver an A{beta} antibody expression vector (AAV-LEC) into the CNS of APP/PS1 and 5xFAD mice intravenously. The AAV-LEC-mediated expression of anti-A{beta} antibodies in the CNS significantly reduced the number and size of A{beta} plaques at various stages in both APP/PS1 and 5xFAD mice, alongside improved spatial learning and memory. It also reversed abnormal glial activation with reduced disease-associated microglia and astrocytes, and restored oligodendrocyte differentiation and myelin formation. No brain microhemorrhage or liver damage was detected following the AAV-antibody treatment. Thus, this AAV-mediated strategy offers a promising, convenient and safe AD therapeutic approach in the future.

Recurrent hypoglycemia increases cognitive impairment in diabetes mellitus patients. Following cerebral neuron injury, endothelial cells provide morphological, metabolic and immune support to damaged neurons. We investigated the inflammatory mechanism involved in hippocampal neuron degeneration. Behavioral experiments, including the open field test (OFT) and the Morris water maze test, were performed to measure cognitive changes. Using a vascular ring experiment, we evaluated vasodilation of the carotid artery. ZBP1 expression was knocked down after transfection with small interfering RNA in a brain endothelial cell line (bEnd3). In this study, PANoptosis, a recently defined form of programmed cell death (PCD), was found to be increased by hypoglycemia in the hippocampus of type 2 diabetic mice in vivo and by low glucose in bEnd3 cells in vitro. ZBP1 knockdown decreased PANoptosis induced by low-glucose stimulation in high-glucose-cultivated bEnd3 cells. RNA transcriptomics sequencing revealed that AGE-RAGE signaling significantly changed after ZBP1 was knocked down in bEnd3 cells. Corresponding biochemical data confirmed that ZBP1 knockdown regulated the advanced glycation end products (AGEs)-Receptor for Advanced Glycation End Products (RAGE) axis in bEnd3 cells. We present the first evidence that hypoglycemia impaired cognition in mice with type 2 diabetes by activating brain endothelial ZBP1-mediated PANoptosis via the AGE-RAGE axis. ARTICLE HIGHLIGHTSO_LIPANoptosis, a newly defined form of programmed cell death, is induced in the hippocampus after recurrent hypoglycemia in male db/db mice. C_LIO_LIZBP1, a sensor of the PANoptosome, was activated in low glucose cultured brain endothelial cells. C_LIO_LIHypoglycemia impairs vasodilation and cognitive function in type 2 diabetic mice. C_LIO_LIOur study indicates that inhibiting ZBP1-PANoptosis and the AGE-RAGE axis may be a potential approach to prevent hypoglycemia-induced cognitive degeneration in individuals with type 2 diabetes. C_LI

The impact of cellular activities on large-scale brain dynamics is thought to determine brain functioning and disease, yet the causal relationships of neural mechanisms across scales remain unclear. Recently, the cerebellum has been reported to affect whole-brain dynamics during sensorimotor integration. To disclose the underlying mechanisms, we have developed a multiscale digital brain co-simulator, in which a spiking neural network of the olivo-cerebellar microcircuit is embedded in a mouse virtual brain and wired with other nodes using an atlas-based long-range connectome. Parameters and bi-directional interfaces between the spiking olivo-cerebellar network and other rate-coded modules were tuned to match experimental data of primary sensory and motor cortex (M1 and S1) power spectral densities and neuronal spiking rates. Then, the role of the cerebellar circuitry on sensorimotor integration was analyzed by lesioning critical circuit connections in silico. Simulations showed that spike processing within the cerebellar circuit is key to explaining the gamma-band coherence between M1 and S1 during sensorimotor integration. These results provide a mechanistic explanation of how the cerebellum promotes the formation of sensorimotor contingencies in relevant cortical modules as the basis of its critical role in sensorimotor prediction. On a broader perspective, this modelling approach opens new perspectives for the multiscale investigation of brain physiological and pathological states in relation to specific cellular and microcircuit properties.

Alzheimers disease (AD) is the most prevalent form of dementia, characterized by progressive memory loss, cognitive decline, and emotional dysregulation. Adult hippocampal neurogenesis (AHN) critically contributes to cognition and mood but undergoes precipitous decline during AD progression. Here, we investigated whether enhancing AHN through genetic expansion of endogenous neural stem cells (NSC) ameliorates AD-related phenotypes. Using lentiviral overexpression of the cell cycle regulators Cdk4 and CyclinD1 in the dentate gyrus of 3xTg-AD mouse, we show that enhancing AHN partially rescues hippocampal-specific cognitive functions, namely: spatial navigation and exploratory behavior. These findings show that endogenous NSC can be exploited to ameliorate hippocampal cognitive functions in AD, providing additional evidence for exploiting AHN as a promising therapeutic target for neurodegenerative disease.

Long noncoding RNAs (LncRNAs) have emerged as a class of important regulatory ncRNAs and are known to fine-tune numerous cellular processes including proliferation, differentiation and development; however, their role in quiescence still remains largely unexplored. A miRNA host gene lncRNA, MIR503HG, has been reported to play important role in cancer development. Here, we demonstrate the role of MIR503HG lncRNA in regulating cellular quiescence. MIR503HG displays elevated levels in human diploid fibroblasts induced to undergo quiescence. Depletion of MIR503HG in HDFs affects the entry of cells into quiescence but has no effect on cell cycle progression, suggesting its role in quiescence attainment and/or maintenance. Additionally, MIR503HG depletion led to a drastic decrease in the levels of miR508 target, PTEN with a concomitant increase in pAkt levels, indicating its role in negative regulation of miR508. Further, we demonstrate that the lncRNA MIR503HG regulates PTEN levels by acting as a ceRNA for miR508 to maintain cellular quiescence. Our studies illustrate that MIR503HG can function synergistically with miR503 to maintain cells under quiescence and both the miRNA-HG and the miRNA encoded by its gene locus synergistically control the same biological process in different ways by regulating different downstream genes.

Although a differential vulnerability of dopaminergic neurons to degeneration based on their specific location within the dorsal and ventral tiers of the substantia nigra pars compacta (SNcD and SNcV, respectively) has long been postulated, the underlying mechanisms sustaining these tier-specific differences remain poorly understood. Here, upon inducing a viral-mediated enhancement of neuromelanin (NMel) accumulation within dopaminergic neurons in non-human primates, the distribution of Lewy body-like inclusions (LBs) was analyzed within identified SNcD and SNcV neurons, together with their intracellular NMel levels. Results showed that the vast majority of intracytoplasmic inclusions were found in SNcV neurons, and indeed correlated to higher pigmentation levels. By contrast, only very few LBs were found in calbindin-positive neurons of the SNcD, which in parallel exhibited very low levels of NMel accumulation. These results postulate an additive effect made of a tier-specific location of LB burden together with high pigmentation levels as synergistic drivers sustaining the preferential vulnerability of SNcV dopaminergic neurons. Moreover, the evidence obtained here supported that NMel accumulation beyond a given threshold triggers the aggregation of endogenous -Syn in the form of LBs; therefore, approaches intended to reduce pigmentation levels in SNcV neurons would likely induce a neuroprotective effect by preventing the subsequent aggregation of -Syn.

The clitoris is one of the least studied organs of the human body. The detailed anatomy of the clitoris is challenging to address through a gross dissection, as most of its parts are embedded internally, surrounded by pubic bone and several pelvic organs. While clinical imaging methods such as magnetic resonance imaging can capture the gross 3D morphology, they lack the spatial resolution required to resolve the detailed structures. In this study, we generated micron-scale computed tomography images of the female pelvises, leveraging a synchrotron radiation X-ray source. This unique data revealed the complex trajectory of the dorsal nerve of the clitoris, the main sensory nerve of the clitoris. Notably, the nerve trunks within the clitoral glans were revealed, with the maximum diameter ranging from 0.2 to 0.7 mm. They showed a tree-like branching pattern projecting towards the surface of the glans. We also revealed that some branches of the dorsal nerve of the clitoris ramify to innervate the clitoral hood and mons pubis. Finally, the posterior labial nerve, a branch of the perineal nerves, was shown to innervate the surroundings of the clitoris and the labial structures. These findings have an immediate impact on operations performed around the vulva area, such as gender-affirmation surgery and reconstruction surgery after genital mutilation.

Astrocytes are highly abundant in the mammalian brain and coordinate with neurons and other glial cells to regulate neural circuit structure, function, and blood brain barrier integrity among many to maintain proper brain homeostasis. Astrocytes perform most of these functions owing to their highly complex morphologies and hundreds of thousands of fine processes that are important in contacting neuronal synapses and other glial cells. In fact, the morphological complexity of astrocytes is regulated by the presence and activity of neurons and helps establish astrocyte territory/tiling in a non-overlapping pattern; however, the mechanisms of astrocyte tiling are not well characterized. Using a human astrocyte-mouse neuron coculture system, we previously showed that sphingosine-1-phosphate receptor 1 (S1PR1) regulates astrocyte morphogenesis in a neuronal contact dependent manner. In this study, we find that S1PR1, in vivo, regulates astrocyte morphogenesis in a cortical layer specific manner. Using astrocyte-specific S1PR1 knock out mouse models and adenoassociated viral labeling methods, we show that S1PR1 is crucial in establishing competition driven astrocyte tiling and morphogenesis in the developing brain. Furthermore, we show that JAK-STAT3 signaling regulates neuronal contact induced expression of S1PR1 in cocultured astrocytes. These studies therefore uncover a lipid signaling receptor as a major regulator of astrocyte morphogenesis and tiling in murine cortical layers.

Mitochondria engage in extensive communication with other organelles through membrane contacts. Perturbed mitochondria-organelle interactions are indicated in a variety of neurodegenerative diseases, but the underlying mechanisms remain poorly understood. Here, we report a new class of mitochondria-organelle communication: autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contact, which exhibits hyper-tethering in tauopathy neurons, consequently hampering AV retrograde transport. Such defects are attributed to accelerated turnover of the contact release factor TBC1D15, triggered by mitochondrial bioenergetic deficit-induced hyperactivity of the AMP-activated protein kinase (AMPK). Increasing TBC1D15 levels or repressing AMPK activity normalizes AV-Mito contact release and restores retrograde transport of AVs, thereby increasing autophagic cargo clearance and reducing tau burden in tauopathy axons. Furthermore, overexpression of TBC1D15 enhances autophagic clearance and attenuates tau pathology, alleviating neurodegeneration and cognitive dysfunction in tauopathy mice. Taken together, our study provides new insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.

AbstractAs organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/717004v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@a3387dorg.highwire.dtl.DTLVardef@1d1b083org.highwire.dtl.DTLVardef@19ba6f0org.highwire.dtl.DTLVardef@1ecf20e_HPS_FORMAT_FIGEXP M_FIG Mechanism of anti-aging action of red light: Red light can reduce SIRT4 signalling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn reverses the expression of age-related inflammatory factors and genes. C_FIG

Tauopathies are characterised by progressive deterioration of brain regions due to abnormal accumulation of the microtubule-associated protein tau (MAPT). Alternative splicing of MAPT pre-mRNA results in six tau isoforms, which are classified into two groups depending on the number of microtubule-binding domain repeats (3R vs 4R). Although many tauopathies are 3R or 4R-specific, the relative contributions of individual isoforms to neurotoxicity remain incompletely understood. To systematically characterise differences in tau isoform toxicity, we created a novel set of Drosophila lines expressing equivalent amounts of the six human tau isoforms (hTau) at levels sufficient to induce visible phenotypes. Using a variety of assays including survival, negative geotaxis and tissue-level or cell-type-specific degeneration, we found that hTau isoform toxicity is not uniform across different biological contexts. Despite generally higher toxicity of 4R isoforms compared to 3R, the effects of individual hTau isoforms varied with the temporal window of expression, tissue type, and neuronal identity. Restricting hTau expression to small homogeneous neuronal populations enabled detailed analysis of isoform-specific degeneration. Neurons previously observed to be vulnerable or resilient to hTau toxicity exhibited differences in the onset and progression of degeneration, suggesting that resilience may be an early and transitory state, with most or all neurons eventually succumbing to tau toxicity over time. Notably, these differences in toxicity were not readily explained by variations in hTau abundance and phosphorylation. Together, our findings demonstrate that tau toxicity is highly context-dependent, clearly isoform-specific, and shaped by interactions between tau and its cellular environment.

Tau protein, the primary component in neurofibrillary tangles characteristic of Alzheimers Disease and related dementia disorders, normally regulates microtubule growth and stability. While tau dysfunction contributes to the progression of tauopathies, the role of microtubules in disease has remained unclear. Through forward genetic screening in Caenorhabditis elegans tauopathy models, we found multiple tubulin gene mutations that rescue tau-mediated neurodegeneration. Whole animal behavioral and in vitro biochemical assays were employed to characterize mutation-driven effects on neuron function, neurodegeneration, and effects on tubulin and tau proteins as well as microtubule function. Mutant tubulin genes were found to confer different levels of suppression correlating with the level of mutant gene expression. Mutant tubulins did not drastically alter total tau protein levels, tau phosphorylation or aggregation, however tau-induced neurodegeneration was rescued. The suppression of tau toxicity by tubulin gene mutations cannot be explained by changes in tau or tubulin expression, tau phosphorylation, or tau aggregation state. Rather the tubulin mutations appear to act by influencing global microtubule properties. In vitro experiments using C. elegans tubulin in semi-isolated and isolated contexts have indicated changes to microtubule properties without observable changes to tau-tubulin affinity. This work suggests that manipulation of microtubules can rescue tauopathy even when pathological tau species persist, supporting the importance of understanding microtubule contributions to disease progression and investigation into microtubule targeted gene therapy or small molecule approaches for tauopathy intervention.

We present a novel integrative analysis of transposable elements (TEs) in 4 single cell RNA-seq (scRNA-seq) datasets of postmortem substantia nigra pars compacta samples of Parkinson Disease (PD) patients matched healthy controls, with the objective of building a cell-type specific trustworthy atlas of TEs that may clarify the role of TEs in sex differences in PD. We have used the soloTE tool to evaluate the TEs expression changes across all snRNA-seq studies identified in our previous systematic review, and then integrated the results using meta-analysis techniques. Finally, we evaluated the possible associations between TEs and protein coding genes by integrating our previous results in this matter with the information of TEs obtained, in order to propose the possible action mechanism by which some of the TEs contribute to PD.

Parkinsons disease (PD) is increasingly recognized as a multisystem disorder, yet the mechanisms linking neurodegeneration with muscle dysfunction remain largely unknown. In this study, using an A53T -synuclein (Syn) transgenic mouse model, we demonstrate coordinated pathological changes across the brain-muscle organs characterized by systemic inflammation, iron accumulation, oxidative stress, and ferroptosis-associated lipid peroxidation. Our quantitative proteomics data revealed dysregulated iron metabolism and ferroptosis in the brain and skeletal muscle. Biochemical validation confirmed increased expression of Transferrin receptor 1 (TFRC), elevated lipid peroxidation, and suppression of antioxidant defenses, including SLC7A11 and GPX4, indicating enhanced ferroptotic susceptibility. Cell-surface proteomics and biophysical assays further revealed that pathological Syn directly interacts with TFRC, promoting iron accumulation and ferroptosis-associated oxidative damage in neuronal and muscle cells. Together, our findings identify ferroptosis as a shared pathological mechanism across the brain and muscle, mediated by the Syn-TFRC interaction, thus linking neurodegeneration and peripheral muscle pathology in PD.

Liquid-liquid phase separation (LLPS) of biomacromolecules is a key mechanism driving the formation of membraneless organelles (MLOs) within cells, playing a crucial role in fundamental biological processes such as cell proliferation and stress response. Accurately understanding and predicting the phase separation propensity of proteins is essential for unraveling the assembly mechanisms of MLOs and their functions under both physiological and pathological conditions. Traditional research methods primarily rely on biochemical experiments, which are limited by low throughput, high cost, and difficulty in systematically exploring sequence-phase transition relationships. This study proposes and implements a novel three-stage, iterative paradigm based on artificial intelligence (AI) to propel phase separation research towards systematization, predictability, and mechanistic understanding. O_LIBenchmark Model Construction: A preliminary predictive model was established based on a Multilayer Perceptron (MLP) neural network, and the driving effect of phenylalanine/tyrosine (F/Y) residue-mediated {pi}-{pi} interactions on LLPS was validated. C_LIO_LIModel Robustness Enhancement: The model was optimized through adversarial training strategies, which effectively identified and eliminated misclassifications of "highly disordered non-phase-separating" trap sequences. This significantly improved the models generalization capability and reliability when handling complex, real-world sequences. C_LIO_LIPhysical Mechanism Integration and Functional Expansion: Incorporating the Uniform Manifold Approximation and Projection (UMAP) manifold learning method and constraints from non-equilibrium thermodynamics, a "fingerprint space" capable of characterizing the thermodynamic behavior of phase separation was constructed. This space enables cluster analysis of different MLO types, and the model can output a thermodynamic stability score for protein phase separation. Based on this score, we identified 10 high-confidence candidate proteins with the potential to form novel MLOs. The paradigm established in this study upgrades phase separation prediction from the traditional "binary classification" approach to a novel research framework characterized by "physical mechanism analysis + novel MLO discovery." It provides the phase separation field with a computational tool that combines high accuracy, strong robustness, and good physical interpretability. C_LI

Understanding how animals produce a versatile locomotor repertoire requires unraveling the interplay between higher centers, decentralized locomotor circuits, and sensory feedback. However, the principles governing their integration remain elusive. We investigated amphibious centipedes through stepwise neural lesions and neuromechanical modeling. Behavioral experiments revealed that while decentralized circuits autonomously generate coordination, the brain and subesophageal ganglion provide situational flexibility, such as modulating trunk undulation and initiating leg folding. Integrating these findings, our model demonstrated how higher centers selectively inhibit or release lower circuit dynamics. Simulations verified that varying only a few descending control parameters reproduces transitions between slow walking, fast walking, and swimming. This work may capture the essence of the locomotor circuitry that harnesses decentralized self-organization to coordinate the bodys large degrees of freedom.

Glycoproteins lining the luminal endothelial surface form the glycocalyx, composing the tripartite blood brain barrier. We explored the glycocalyx as a source of danger signals for complement lectin pathway after ischemic stroke. Our data indicate that hypoxic microvascular cells increased -D-mannosyl and N-acetylglucosaminyl exposure after re-oxygenation, favoring mannose binding lectin (MBL) pathogenic deposition, and overexpression of inflammatory genes (ICAM-1 and MMP-2). The hypoxia-conditioned medium induced neuronal damage (reduced MAP-2), microglia and astrocytic reactivity (increased/thickened ramifications) when applied to induced pluripotent stem cell-derived neurons, astrocytes and microglia co-cultures. All these effects were counteracted by mannose-capped gold nanoparticles (Man-GNPs), shown to bind and sequester MBL from the medium. We then tested the Man-GNPs in vivo, in an ischemic stroke model using humanized mice, knocked-in for human MBL. The ischemic mice (males:females 1:1) treated with Man-GNPs (3h after the ischemic onset) exhibited less anxiety at the elevated plus maze and reduced neuronal loss at 8d after ischemia compared to vehicle-treated. Thus, multivalent Man-GNPs represent a promising approach to take MBL away from its glycoproteic targets on the ischemic endothelium, hence preventing downstream pathogenesis. Moreover, these data support circulating MBL as a druggable pharmacological target to prevent the thrombo-inflammatory events following acute brain injury.

Neurofibromin 1 (NF1) is a critical negative regulator of the RAS-RAF-ERK pathway, mutations in which have been clinically implicated in various neurodevelopmental disorders. However, the lack of a high-resolution spatiotemporal map has obscured the understanding of why specific cell populations and developmental processes are uniquely vulnerable to NF1 loss. In this study, we present a comprehensive atlas of NF1 expression in the developing mouse brain. Using in situ hybridization and immunohistochemistry, we characterized NF1 distribution from early embryonic stages through postnatal maturation. We further integrated these findings with single-nuclei RNA-sequencing (snRNA-seq) datasets from adult mouse brain to achieve higher resolution. Our results reveal a previously undocumented graded expression pattern of NF1 across various brain regions and lineages. This comprehensive study will not only help in understanding the fundamental role of NF1 during brain development but will also be pivotal in providing a framework to study NF1-associated brain disorders.

Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.