Cell reports最新文献

Astrocytes regulate brain cholesterol homeostasis, but the astrocyte-specific mechanisms disrupted in Alzheimer's disease (AD) are poorly understood. By integrating human bulk transcriptomes with single-nucleus RNA sequencing (RNA-seq), we identified adipocyte enhancer-binding protein 1 (AEBP1) as an astrocyte-enriched factor upregulated in AD. In postmortem human tissue and 5×FAD mice, astrocytic AEBP1 levels rise with age and disease progression. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β (Aβ) pathology in 5×FAD mice, confirming causality in vivo. In cultured astrocytes, AEBP1 overexpression represses lysosomal acid lipase (LIPA), leading to lipid droplet accumulation, excess cholesteryl ester storage, and lysosomal Aβ retention. LIPA restoration reverses these effects. Hippocampal transcriptomics and metabolomics from AEBP1-knockdown or LIPA-overexpressing 5×FAD mice show converged cholesterol/lipid pathway remodeling, reduced Aβ burden, and cognitive improvement. Mechanistically, AEBP1 sequesters NPAS3 in the cytoplasm, reducing its binding to the Lipa promoter. Thus, the astrocytic AEBP1-NPAS3-LIPA axis links lysosomal cholesterol catabolism to AD pathology.

Acetylation of histones and transcriptional regulators modulates gene expression, but how acetyltransferases define target specificity remains puzzling. In Cell Reports, Gelder et al.¹ have shown how intrinsically disordered regions of CBP temper each other to shape acetyltransferase activity.

The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. However, the underlying molecular mechanisms remain unclear. This study shows a SET-domain bifurcated histone lysine methyltransferase, SETDB2, in trigeminal ganglion (TG) neurons as a key mediator of migraine-like pain. In a mouse model of chronic migraine induced by nitroglycerin (NTG), SETDB2 is significantly upregulated in TG neurons, a finding mirrored in cerebrospinal fluid from patients with migraine. Reversing this upregulation reduces levels of the repressive histone mark H3K9me3 and alleviates migraine-like pain behaviors in mice, whereas mimicking it induces hypersensitivity. Mechanistically, SETDB2 upregulation impedes transcription factor KLF4 from binding to the promoter of the insulin-degrading enzyme (Ide) gene, thereby suppressing IDE expression and impairing degradation of calcitonin-gene-related peptide (CGRP) in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present therapeutic opportunities for treating migraine.

The microtubule-based motor dynein and its cofactor dynactin are activated by various adaptors to fulfill essential functions throughout the cell cycle, including organelle transport and mitotic spindle assembly. NuMA is a mitotic adaptor that interacts with dynein-dynactin via its N-terminal region (NuMA-N). However, how NuMA-N binds and activates dynein-dynactin in mitosis remains unclear. Here, we combine a membrane-tethering assay, quantitative proteomics, and live-cell analyses to show that mitotic phosphorylation of NuMA-N drives dynein-dynactin-NuMA (DDN) assembly. We find that CDK1-Cyclin B1 phosphorylates NuMA-N, primarily at its conserved serine 203, which stimulates dynein activation in vitro. Replacing endogenous NuMA with phosphorylation-deficient mutants further reveals that NuMA-N phosphorylation, together with its dynein-binding site and Spindly-like motif, is required to form stable DDN complexes for functional spindle assembly. These results highlight CDK1-dependent N-terminal NuMA phosphorylation as a crucial mitotic phospho-switch that ensures stable multivalent interactions between dynein-dynactin and NuMA for accurate chromosome segregation.

The prefrontal cortex (PFC) and locus coeruleus (LC) form a bidirectional circuit essential for cognitive control and arousal. LC-derived norepinephrine (NE) influences PFC network dynamics, yet the mechanisms by which descending PFC inputs regulate LC activity and gate its neuromodulatory feedback remain unclear. Here, we describe an anatomical and functional PFC-LC loop subject to endocannabinoid (eCB) negative feedback. Optogenetic activation of PFC terminals in the LC enhances NE release and recruits NE-sensitive neuronal activity in the PFC. Under behaviorally relevant patterns of activation, LC-derived eCBs are mobilized, thereby weakening PFC-to-LC synaptic transmission. This limits subsequent NE release in the PFC and constrains the recruitment of NE-sensitive PFC neuronal assemblies. Modulation of this PFC-LC interaction shapes outcome discrimination in place conditioning tasks. By elucidating how eCB signaling modulates the PFC-LC loop, our findings reveal how these lipid molecules fine-tune NE signaling in the PFC, which is involved in cognitive and arousal-related processes.

This study explores the inflammatory response observed in the pancreas and pancreatic lymph nodes (pLNs) during the natural history of type 1 diabetes (T1D). Using multicell-resolution spatial transcriptomics (ST), we profile individuals without diabetes (ND), at-risk autoantibody-positive (AAb+) individuals, and T1D donors. In the T1D pancreas, we observed global upregulation of inflammation-associated transcripts, including REG family genes, C3, SOD2, and OLFM4. In the T1D pLN, LTB was significantly upregulated within the lymphoid follicles. Using an orthogonal subcellular-resolution ST platform on an independent donor set, we identified follicular B cells as the primary source of LTB in the pLN and observed increased LTB expression in lymphocytes in insulitic lesions proximal to CCL19/CCL21-expressing endothelium. Collectively, these findings highlight lymphotoxin-β and downstream chemokine signatures in the pancreatic lymphatics as well as within the insulitic lesion, which can inform future therapeutic interventions.

Plasmodium falciparum malaria relies on antigenic variation mediated by mutually exclusive expression of var genes. Repressed var genes cluster together and are bound by PfHP1 (Plasmodium falciparum heterochromatin protein 1), but the regulatory mechanism remains unclear. Here, we show that PfHP1 undergoes phase separation in vitro and compartmentalizes DNA. This process is tunable by RNA and PfH2A.Z. Our single-molecule assays show that PfHP1 preferentially compacts AT-rich DNA. We identify point mutations in the intrinsically disordered region of PfHP1 that disrupt phase separation and DNA compaction. Analysis of GFP-PfHP1 parasites by fluorescence recovery after photobleaching shows rapid recovery, consistent with fluid condensate behavior in vivo. Expression of phase-separation-defective mutants cause dispersed nuclear localization, altered chromatin binding, and derepression of up to 54 of 60 var genes. Hi-C analysis reveals loss of heterochromatic interactions, establishing PfHP1-mediated phase separation as a key mechanism for heterochromatin organization and var gene silencing.

Prefrontal cortex is often viewed as an extension of the motor system, but little is understood about how it relates to natural motor behavior. We therefore tracked the kinematics of freely moving rats performing minimally structured tasks and measured how behavior is represented in prefrontal neural populations. Naturalistic behaviors such as rearing or chasing bait were each encoded by unique neural ensembles, but the behavioral representations were not anchored to posture or low-level motor execution. Single-cell coding was similarly abstract: most neurons encoded specific behaviors, not their kinematic components, and behavioral selectivity varied across tasks. Neural ensemble coding of actions often preceded their physical expression by 2-3 s, and accordingly, prefrontal population activity evolved at slower timescales than motor cortex. These findings argue that prefrontal coding of behavior is not locked to motor output and may instead reflect motivations to perform actions rather than actions themselves.

Alu elements are evolutionarily very old primate-specific interspersed repeat elements that constitute ∼11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and cause inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here, we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrate that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we show that neurons derived from SCA37 subjects have higher levels of DAB1 expression and that DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

RNA 5-methylcytosine (m5C) methylation is a key post-transcriptional modification, yet its role in vascular stability remains unclear. Through integrative m5C-RNA immunoprecipitation and transcriptomic, proteomic, and single-cell analyses of ruptured and unruptured human brain arteriovenous malformations (bAVMs), we find DOCK9 to be an endothelial-specific, m5C-regulated gene downregulated in the ruptured group. Functional assays in endothelial cells and CRISPR-Cas9 zebrafish models show that DOCK9 controls endothelial proliferation, migration, and vascular integrity. Endothelial-specific overexpression of dock9 rescues vascular defects in dock9-deficient zebrafish. Mechanistically, the RNA methyltransferase NSUN2 directly binds and methylates DOCK9 mRNA to stabilize its expression. NSUN2 knockdown mimics dock9 deficiency in zebrafish, supporting a functional NSUN2-DOCK9 axis. These findings show a molecular pathway linking m5C dysregulation to cerebrovascular instability and bAVM rupture. Targeting this axis may offer a strategy for stabilizing fragile cerebrovascular lesions.