Neurobiology of Disease最新文献

{"title":"Circulating C-reactive protein influences polygenic risk of inflammatory genes expressed in brain endothelia for Alzheimer’s disease","authors":"Jinghan Huang ,&nbsp;Habbiburr Rehman ,&nbsp;Chinh Doan ,&nbsp;Thor D. Stein ,&nbsp;Jesse Mez ,&nbsp;Ting Fang Alvin Ang ,&nbsp;Qiushan Tao ,&nbsp;Rhoda Au ,&nbsp;Lindsay A. Farrer ,&nbsp;Xiaoling Zhang ,&nbsp;Wei Qiao Qiu","doi":"10.1016/j.nbd.2026.107257","DOIUrl":"10.1016/j.nbd.2026.107257","url":null,"abstract":"<div><h3>Background</h3><div>C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer’s disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk.</div></div><div><h3>Methods</h3><div>Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the <em>APOE</em> region, that are involved in inflammation, synaptic transmission, and other pathways.</div></div><div><h3>Results</h3><div>Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (&lt;50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included <em>APP</em>, <em>IL6ST</em>, and <em>FN1</em>, are involved in amyloid pathology, wound healing, and coagulation.</div></div><div><h3>Conclusion</h3><div>Our findings highlight two distinct genetic-dose dependent backgrounds: \"vulnerable\" (&lt;50% inflammatory PRS) and \"resilient\" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G<span><math><mo>×</mo></math></span>IE) interaction model, linking peripheral inflammation to AD risk.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107257"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study","authors":"Beck Strohmer ,&nbsp;Kaitlyn Grosh ,&nbsp;Roser Montañana-Rosell ,&nbsp;Santiago Mora ,&nbsp;Jessica Ausborn ,&nbsp;Ilary Allodi","doi":"10.1016/j.nbd.2025.107253","DOIUrl":"10.1016/j.nbd.2025.107253","url":null,"abstract":"<div><div>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1–motoneuron connections improved motor function and saved motoneurons in the SOD1^G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor–extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1^G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107253"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted dynamic brain network and its functional topological underpinning in essential tremor","authors":"Weijin Yuan ,&nbsp;Xiaojie Duanmu ,&nbsp;Qianshi Zheng ,&nbsp;Cheng Zhou ,&nbsp;Qingze Zeng ,&nbsp;Zihao Zhu ,&nbsp;Tao Guo ,&nbsp;Jiaqi Wen ,&nbsp;Chenqing Wu ,&nbsp;Haoting Wu ,&nbsp;Jianmei Qin ,&nbsp;Yuelin Fang ,&nbsp;Bingting Zhu ,&nbsp;Lifang Wang ,&nbsp;Ziyi Zhu ,&nbsp;Yaping Yan ,&nbsp;Jun Tian ,&nbsp;Baorong Zhang ,&nbsp;Guohua Zhao ,&nbsp;Minming Zhang ,&nbsp;Xiaojun Xu","doi":"10.1016/j.nbd.2026.107274","DOIUrl":"10.1016/j.nbd.2026.107274","url":null,"abstract":"<div><h3>Background</h3><div>Essential tremor (ET) is one of the most prevalent neurological diseases and is recognized as a disorder involving multiple neural network dysfunctions. Previous resting-state fMRI studies in ET ignored brain network important dynamic nature. This study aimed to investigate the alterations of dynamic functional connectivity (DFC) and its functional topology in ET.</div></div><div><h3>Methods</h3><div>Resting-state fMRI data were collected from 144 ET and 131 normal controls (NC). Sliding-window approach with K-means clustering algorithm was used to identify dynamic functional states and graph theory analysis was performed to explore related topological organization of each state in ET.</div></div><div><h3>Results</h3><div>Two distinct and switchable DFC states (State 1: “cerebrum-dominant” state, with hyperconnected functional architecture in cerebrum; State 2: “cerebellum-dominant” state, with higher functional independence in cerebellum) were identified. Compared to NC, higher fractional windows and longer mean dwell time of cerebellum-dominant state, and fewer state transitions were observed in ET. Higher fractional windows and longer dwell time of cerebellum-dominant state were correlated with more severe tremor. In the topological analysis, compared to NC, ET demonstrated decreased nodal degree centrality and nodal efficiency in cerebrum regions (e.g., orbital inferior frontal gyrus and temporal pole) within two states, but increased nodal betweenness centrality in cerebellum regions (e.g., Cerebellum Crus 2 and Vermis) within cerebellum-dominant state.</div></div><div><h3>Conclusions</h3><div>These findings revealed that ET was characterized by prolonged cerebellum-dominant state and disrupted functional topology within both states, providing novel insights for better understanding the fundamental neurobiological mechanisms in ET.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107274"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of alcohol dependence on the CSF proteome in mice: Evidence for blood-brain barrier dysfunction and neuroinflammation","authors":"Natalie P. Turner ,&nbsp;Michal Bajo ,&nbsp;Amanda J. Roberts ,&nbsp;Marisa Roberto ,&nbsp;John R. Yates III","doi":"10.1016/j.nbd.2025.107254","DOIUrl":"10.1016/j.nbd.2025.107254","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) represents a significant neurological health burden, yet the biological mechanisms underlying alcohol-induced brain pathology remain incompletely understood. Moreover, the molecular underpinnings of the transition from alcohol exposure to alcohol dependence are not well-characterized. We used mass spectrometry (MS)-based proteomics in a preliminary discovery study to compare cerebrospinal fluid (CSF) of alcohol-exposed Non-dependent (Non-dep) versus alcohol-dependent (Dep) mice that underwent the chronic intermittent ethanol (alcohol) – two-bottle choice (CIE-2 BCE) procedure and systemic anti-IL-6 Receptor antibody administration (<em>n</em> = 9; female = 5, male = 4). CSF samples from individual mice were processed for proteomic analysis and digested with trypsin overnight. Peptides were analyzed via data-independent acquisition (DIA)-MS and data were processed in DIA-NN at 1 % FDR. We identified 595 unique proteins across both groups, with 140 proteins differentially detected in CSF from Dep mice and 62 proteins specific to alcohol-exposed but Non-dep controls. The Dep-specific proteins revealed signatures of blood-brain barrier (BBB) disruption, neuroinflammation, cellular stress responses, and complement system activation. In contrast, Non-dep-specific proteins indicated preserved protective mechanisms including complement regulation, anti-inflammatory signaling, and neuronal calcium homeostasis. Ethanol-dependent-specific findings include MMP2, BIP, and to a lesser extent VE-cadherin (CDH5) and VCAM1, indicative of the beginnings of endothelial damage and BBB disruption, alongside established neuroinflammation markers GFAP, CHI3L1, and CX3CL1. This work provides novel preliminary protein-level evidence that alcohol exposure and alcohol dependence are dichotomous; despite the small sample size and limited power for moderate effect sizes, there appears to be a clear molecular transition from maintained protective mechanisms to vascular damage, BBB breakdown, and sustained neuroinflammation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107254"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?","authors":"Sara Tessitore ,&nbsp;Carola Torazza ,&nbsp;Tiziana Bonifacino ,&nbsp;Francesca Bacchetti ,&nbsp;Francesco Roselli ,&nbsp;Luca Raiteri ,&nbsp;Marco Milanese ,&nbsp;Giambattista Bonanno","doi":"10.1016/j.nbd.2026.107272","DOIUrl":"10.1016/j.nbd.2026.107272","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a “multifactorial” and “multicellular” disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107272"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis identifies mitochondrial dysfunction in CD83+ macrophages as a key event in diabetic peripheral neuropathy progression","authors":"Yumin Lin ,&nbsp;Yuanyuan Shen ,&nbsp;Jiahua Wu ,&nbsp;Yucheng Wang ,&nbsp;Yijin Zhao ,&nbsp;Caixia Yao ,&nbsp;Jiale Lin ,&nbsp;Hanbing Zhao ,&nbsp;Hongman Zhang ,&nbsp;Yucong Chen ,&nbsp;Jianbo Li","doi":"10.1016/j.nbd.2026.107262","DOIUrl":"10.1016/j.nbd.2026.107262","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic peripheral neuropathy (DPN) is a debilitating diabetic complication marked by progressive nerve fiber loss and dysfunction. While extensive studies have focused on the onset of DPN, the mechanisms underlying its progression remain poorly understood. Once DPN progression occurs, it can render nerve damage irreversible and make treatment more challenging. Emerging evidence suggests that immune and mitochondrial metabolic dysregulation play critical roles in disease exacerbation, yet the specific cell subtype and molecular mediators driving DPN progression have not been systematically identified.</div></div><div><h3>Methods</h3><div>Constructed a progressive DPN mouse model for bulk sequencing to explore progression-related mechanisms. Integrated Scissor and multi-omics analyses identified key cell subtypes and hub genes. TIMM23's role in DPN progression and mitochondrial function was validated in vitro in bone marrow-derived macrophages (BMDMs) and in vivo via adeno-associated virus-mediated overexpression.</div></div><div><h3>Results</h3><div>Mitochondrial metabolic dysfunction is a potential core mechanism underlying the progression of DPN. CD83+ macrophages were identified as the most prominent and specific subset associated with mitochondrial dysfunction and the DPN progression. Accordingly, we constructed a progressive DPN-related mitochondrial score, which enabled quantitative evaluation of DPN progression, inflammation, and immune infiltration. In vitro, high-glucose or high-fat intervention in BMDMs resulted in reduced expression of TIMM23. TIMM23 overexpression increased ATP production and mitochondrial mass, while reducing reactive oxygen species. In vivo, TIMM23 overexpression in the sciatic nerve improved nerve conduction velocity and nociceptive responses.</div></div><div><h3>Conclusion</h3><div>This study highlights the first discovery of CD83+ macrophages in DPN progression and identifies TIMM23 as a potential diagnostic and therapeutic marker.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107262"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A fresh view of the zona incerta: From circuit complexity to disease pathogenesis","authors":"You Wu ,&nbsp;Chen Chen ,&nbsp;Ningcan Ma ,&nbsp;Yiwen Zhang ,&nbsp;Jialin Si ,&nbsp;Xiaolin Zhang ,&nbsp;Shengxi Wu ,&nbsp;Yang Bai ,&nbsp;Jing Huang","doi":"10.1016/j.nbd.2026.107261","DOIUrl":"10.1016/j.nbd.2026.107261","url":null,"abstract":"<div><div>The zona incerta (ZI) is a diencephalic nucleus that houses neurochemically diverse neuronal populations. It serves as a critical integrative hub because of its bidirectional connectivity with multiple central nervous system regions. Emerging evidence highlights its essential roles in sensorimotor integration, affective processing, and behavioral regulation, thus positioning ZI neuromodulation as a key focus in systems neuroscience. Despite progress in characterizing its cytoarchitecture, molecular profiles, and network connectivity, a systematic understanding of the functional topography of ZI is yet to be achieved. This review utilizes current knowledge across three domains: 1) multimodal sensory processing, 2) emotional valence encoding, and 3) behavioral regulation and proposes an integrative framework to advance translational investigations of ZI-mediated neurophysiological mechanisms.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107261"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic GABA controls fidelity of temporal cortical processing in Fragile X Syndrome","authors":"Victoria A. Wagner ,&nbsp;Ritika Thapa ,&nbsp;Anna O. Norman ,&nbsp;Alexandra Varallo ,&nbsp;Jordan Wimberly ,&nbsp;Maham Rais ,&nbsp;Dmytro Gerasymchuk ,&nbsp;Timo P. Piepponen ,&nbsp;Khaleel A. Razak ,&nbsp;Maija L. Castren ,&nbsp;Iryna M. Ethell","doi":"10.1016/j.nbd.2025.107233","DOIUrl":"10.1016/j.nbd.2025.107233","url":null,"abstract":"<div><div>Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse <em>Fmr1</em> knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific <em>Fmr1</em> KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107233"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS","authors":"Vitaly Zimyanin ,&nbsp;Banaja P. Dash ,&nbsp;Theresa Simolka ,&nbsp;Hannes Glaß ,&nbsp;Arun Pal ,&nbsp;Felix Haidle ,&nbsp;Kathi Zarnack ,&nbsp;Riya Verma ,&nbsp;Vivek Khatri ,&nbsp;Christopher Deppmann ,&nbsp;Eli Zunder ,&nbsp;Michaela Müller-McNicoll ,&nbsp;Stefanie Redemann ,&nbsp;Andreas Hermann","doi":"10.1016/j.nbd.2026.107268","DOIUrl":"10.1016/j.nbd.2026.107268","url":null,"abstract":"<div><div>Mutations in <em>FUSED IN SARCOMA (FUS</em>) cause juvenile-onset amyotrophic lateral sclerosis (ALS). Early pathogenesis of <em>FUS</em>-ALS involves impaired transcription and splicing, DNA damage response, and axonal degeneration. However, the molecular pathophysiology and the link between somatic and axonal phenotypes are still poorly understood. We evaluated whether compartment-specific transcriptome differences could distinguish and drive early axonal degeneration. We used iPSC-derived motor neurons (MNs) coupled with microfluidic approaches to generate RNA-sequencing profiles from axonal and somatodendritic compartments. We demonstrate that the axonal transcriptome is unique and distinct, with RNA metabolism, extracellular secretion, and matrix disassembly pathways particularly enriched in distal axonal compartments.</div><div><em>FUS</em> mutation leads to changes in distinct pathways that were clustered in only a few distinct protein-protein interaction (PPI) networks. Somatodendritic changes upon <em>FUS</em> mutation include WNT signaling, mitochondrial, extracellular matrix (ECM)-, and synapse-related functions. In contrast, analysis of the axonal transcriptome in mutant MNs centers on the <em>PLK1</em> pathway, mitochondrial gene expression, and regulation of inflammation. Comparison to CLIP-seq data revealed a significant enrichment for <em>PLK1</em> and DNA replication pathways in axons. <em>PLK1</em> upregulation did not activate cell-cycle re-entry but contributed to mutant MNs survival, and its inhibition increased neuronal cell death. We propose that upregulation of <em>PLK1</em> represents an early event in the pathogenesis of ALS and could act in response to DNA damage, mitochondrial damage, and immune response activation in the affected cells. Additionally, downregulation of ECM pathways in the somatodendritic compartment and axons could explain strongly compromised dynamics of axonal outgrowth. Overall, we provide a novel valuable resource of the potential targets and affected processes changed in the specific compartments of <em>FUS</em>-ALS motor neurons.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107268"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic activation of hippocampal area CA2 promotes acute and chronic seizures in a mouse model of epilepsy","authors":"John J. LaFrancois ,&nbsp;Meghan Kennedy ,&nbsp;Monarchsinh Rathod ,&nbsp;Bina Santoro ,&nbsp;Christos Panagiotis Lisgaras ,&nbsp;Steven A. Siegelbaum ,&nbsp;Helen E. Scharfman","doi":"10.1016/j.nbd.2025.107256","DOIUrl":"10.1016/j.nbd.2025.107256","url":null,"abstract":"<div><div>Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (<em>Amigo2</em>-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (<em>status epilepticus</em>, SE), which leads to chronic seizures after 3–4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve <em>Amigo2-</em>Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107256"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}