Biology subjects

Krueger, D. M.

Publications and source records attributed to Krueger, D. M..

9 recordsLinked to original sources

bioRxiv2026

The lncRNA Gm16685/MITA1 modulates inflammatory astrocyte reactivity through PCBP2 associated regulation of IKKβ signaling

Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of cellular identity and disease associated gene expression programs, yet their role in astrocyte reactivity remains poorly understood. Here, we profiled lncRNA expression in primary mouse astrocytes exposed to inflammatory activation paradigms that model microglia driven signaling. This identified a conserved set of activation responsive lncRNAs, among which Gm16685 emerged as one of the most strongly induced candidates. Gm16685 and its human homolog MITA1 were enriched in the nucleus, and MITA1 expression was increased in selected human datasets from Alzheimers disease, Parkinsons disease and frontotemporal dementia patients. Functional depletion of Gm16685 attenuated inflammatory gene expression and several activation associated astrocyte phenotypes, including reactive oxygen species production, glutamate handling, phagocytic activity and proliferation. Time-resolved transcriptomic analysis indicated that Gm16685 is required for the timely induction of inflammatory response genes. Mechanistically, Gm16685/MITA1 interacted with the RNA binding protein PCBP2, and Gm16685 depletion was associated with reduced PCBP2 protein abundance, altered splicing of Inhibitor of NF-{kappa}B Kinase Subunit Beta (IKK{beta}) and a shift in downstream inflammatory signaling. Together, our findings identify Gm16685/MITA1 as a conserved lncRNA regulator of astrocyte reactivity and suggest that non-coding RNA dependent control of RNA binding proteins contributes to inflammatory signaling in neurodegenerative disease relevant contexts.

neuroscience↗

bioRxiv2026

Loss of the lncRNA SOX1-OT promotes p53-dependent cell-cycle arrest in astrocytes

Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of brain cell function, but their roles in astrocyte biology and neurodegeneration remain poorly understood. Here, we identify Sox1ot/SOX1-OT as a conserved, brain-enriched lncRNA that is downregulated in Alzheimers disease and in reactive astrocyte states. Antisense oligonucleotide-mediated depletion of Sox1ot in astrocytes revealed a transcriptional program marked by activation of p53 target genes selectively associated with cell-cycle inhibitory pathways. Consistent with this, Sox1ot depletion enhanced p53 occupancy at target promoters such as Cdkn1a, increased Cdkn1a expression and levels of its protein product p21, and thereby induced G1 arrest and reduced astrocyte proliferation. In contrast, other canonical p53 outputs, including apoptosis and senescence, were not affected, indicating that Sox1ot selectively modulates distinct branches of p53 signaling. Notably, loss of Sox1ot/SOX1-OT was accompanied by impaired glutamate uptake, reduced lactate secretion, and altered astrocyte support functions, suggesting that these deficits arise as downstream consequences of the p53-dependent transcriptional shift rather than direct primary effects of Sox1ot loss. Together, these findings identify SOX1-OT as an astrocyte-enriched regulatory layer that constrains a p53-dependent cell-cycle program and highlight its role in shaping astrocyte state transitions in Alzheimers disease.

neuroscience↗

bioRxiv2025

lncRNA 3222401L13Rik/ENSG00000272070 modulates microglial inflammatory programs in association with PU.1

Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070. We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNF, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimers disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik-regulated targets. Together, our results identify 3222401L13Rik/ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases. HighlightsO_LI3222401L13Rik is a glia-enriched long non-coding RNA regulating microglial state C_LIO_LIKnockdown of 3222401L13Rik increases TNF signaling C_LIO_LIThe human homolog ENSG00000272070 shows reduced expression in AD brains C_LIO_LI3222401L13Rik interacts with the AD-associated transcription factor PU.1 C_LIO_LIA conserved 3222401L13Rik-PU.1 axis modulates microglial inflammation in aging and disease C_LI

neuroscience↗

bioRxiv2025

NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named Neuronal Identity (NeuID)--a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimers disease (AD) patients. Mechanistically, NeuID maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of NeuID disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated NeuID overexpression restores neuronal function in A{beta}42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD. One sentence summaryWe identify NeuID, a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimers disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.

neuroscience↗

bioRxiv2024

LncRNA 3222401L13Rik Is Up-regulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3

Aging is linked to a decline in cognitive functions and significantly increases the risk of neurodegenerative diseases. While molecular changes in all central nervous system (CNS) cell types contribute to aging-related cognitive decline, the mechanisms driving disease development or offering protection remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular functions and gene expression, yet their roles in aging, particularly within glial cells, are not well characterized. In this study, we investigated lncRNA expression profiles in non-neuronal cells from aged mice. We identified 3222401L13Rik, a previously unstudied lncRNA enriched in glial cells, as being specifically upregulated in astrocytes during aging. Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes essential for neuronal support and synapse organization. This function was also conserved in human iPSC-derived astrocytes. Additionally, we found that 3222401L13Rik mediates its cellular effects through interaction with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and that overexpression of Npas3 effectively rescued the functional deficits observed in astrocytes lacking 3222401L13Rik. Our findings suggest that upregulation of 3222401L13Rik in aging astrocytes acts as a compensatory mechanism to enhance neuronal and synaptic support, potentially delaying the onset of molecular and structural changes in both astrocytes and neurons. Strategies to boost 3222401L13Rik expression earlier in life may help mitigate age-associated loss of neuronal plasticity.

neuroscience↗

bioRxiv2024

PRDM16-DT is a Brain and Astrocyte-Specific lncRNA Implicated in Alzheimers Disease

Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimers disease (AD), highlighting the growing interest in targeting astrocyte function to address early phases of AD pathogenesis. While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction

neuroscience↗

bioRxiv2023

A single-cell transcriptomic analysis of the mouse hippocampus after voluntary exercise

Exercise has been recognized as a beneficial factor for cognitive health, particularly in relation to the hippocampus, a vital brain region responsible for learning and memory. Previous research has demonstrated that exercise-mediated improvement of learning and memory in humans and rodents correlates with increased adult neurogenesis and processes related to enhanced synaptic plasticity. Nevertheless, the underlying molecular mechanisms are not fully understood. With the aim to further elucidate these mechanisms we provide a comprehensive dataset of the mouse hippocampal transcriptome at the single-cell level after four weeks of voluntary wheel-running. Our analysis provides a number of interesting observations. For example, the results suggest that exercise affects adult neurogenesis by accelerating the maturation of a subpopulation of Prdm16-expressing neurons. Moreover, we uncover the existence of an intricate crosstalk among multiple vital signaling pathways such as NF-{kappa}B, Wnt/{beta}-catenin, Notch, retinoic acid (RA) pathways altered upon exercise in a specific cluster of excitatory neurons within the Cornu Ammonis (CA) region of the hippocampus. In conclusion, our study provides an important resource dataset and sheds further light on the molecular changes induced by exercise in the hippocampus. These findings have implications for developing targeted interventions aimed at optimizing cognitive health and preventing age-related cognitive decline.

neuroscience↗

bioRxiv2021

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

neuroscience↗

bioRxiv2020

The Coding And Small-Non-Coding Hippocampal Synaptic RNAome

Neurons are highly compartmentalized cells that depend on local protein synthesis. Thus, messenger RNAs (mRNAs) have been detected in neuronal dendrites and more recently also at the pre- and postsynaptic compartment. Other RNA species, such as microRNAs, have also been described at synapses where they are believed to control mRNA availability for local translation. Nevertheless, a combined dataset analyzing the synaptic coding and non-coding RNAome via next-generation sequencing approaches is missing. Here we isolate synaptosomes from the hippocampus of young wild type mice and provide the coding and non-coding synaptic RNAome. These data are complemented by a novel approach to analyze the synaptic RNAome from primary hippocampal neurons grown in microfluidic chambers. Our data show that synaptic microRNAs control almost the entire synaptic mRNAome and we identified several hub microRNAs. By combining the in vivo synaptosomal data with our novel microfluidic chamber system, we also provide evidence to support the hypothesis that part of the synaptic microRNAome may be supplied to neurons via astrocytes. Moreover, the microfluidic system is suitable to study the dynamics of the synaptic RNAome in response to stimulation. In conclusion, our data provide a valuable resource and hint to several important targets for future experiments.

neuroscience↗