Neurobiology of Disease最新文献

{"title":"Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia","authors":"Costanza Mazzantini ,&nbsp;Martina Venturini ,&nbsp;Daniele Lana ,&nbsp;Gloria Mulas ,&nbsp;Clara Santalmasi ,&nbsp;Giada Magni ,&nbsp;Paola Bruni ,&nbsp;Anna Maria Pugliese ,&nbsp;Francesca Cencetti ,&nbsp;Domenico E. Pellegrini-Giampietro ,&nbsp;Elisa Landucci","doi":"10.1016/j.nbd.2025.106865","DOIUrl":"10.1016/j.nbd.2025.106865","url":null,"abstract":"<div><div>It is well accepted that sphingolipids play an important role in the pathological process of cerebral ischemia. In the present study we have investigated the involvement of sphingosine 1-phosphate (S1P) pathway in two different in vitro models of global ischemia.</div><div>In organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) we evaluated the mRNA expression of S1P metabolic enzymes and receptors (S1P_1–5) by Real Time-PCR. In the same model we investigated the effect of the inhibitor of S1P lyase (SPL), LX2931, the selective antagonists of S1P₂, JTE-013, and S1P₃, CAY10444, quantifying the cell death in the CA1 region by propidium iodide fluorescence, and morphological and tissue organization alterations by immunohistochemistry and confocal microscopy. Moreover, we performed extracellular recordings of field excitatory postsynaptic potentials in acute slices exposed to OGD.</div><div>In organotypic slices OGD induced a significant increase of SPL at mRNA level and of S1P₂ and S1P₃ at both mRNA and protein level. The incubation with LX2931, JTE-013 or CAY10444 was able to reduce CA1 damage induced by OGD in organotypic slices and provoked a significant delay of the onset of anoxic depolarization on acute slices. Moreover, S1P₂ and S1P₃ antagonists prevented the increase of TREM2 induced by OGD.</div><div>Our results reveal a dual role of S1P pathway in brain ischemia: intracellular S1P, degraded via SPL, appears to be beneficial whereas signaling via S1P₂ and S1P₃ is detrimental to the disease. These findings support the notion that SPL, S1P₂ and S1P₃ are promising therapeutic targets in brain ischemia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106865"},"PeriodicalIF":5.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential miRNA expression in neural-enriched extracellular vesicles as potential biomarker for frontotemporal dementia and bipolar disorder","authors":"Maria Serpente ,&nbsp;Giuseppe Delvecchio ,&nbsp;Chiara Fenoglio ,&nbsp;Lorena Di Consoli ,&nbsp;Giulia Giudici ,&nbsp;Vittoria Borracci ,&nbsp;Emanuela Rotondo ,&nbsp;Marina Arcaro ,&nbsp;Luca Sacchi ,&nbsp;Manuela Pintus ,&nbsp;Laura Ghezzi ,&nbsp;Adele Ferro ,&nbsp;Cecilia Prunas ,&nbsp;Antonio Callari ,&nbsp;Elisa Scola ,&nbsp;Fabio M. Triulzi ,&nbsp;Andrea Arighi ,&nbsp;Paolo Brambilla ,&nbsp;Daniela Galimberti","doi":"10.1016/j.nbd.2025.106867","DOIUrl":"10.1016/j.nbd.2025.106867","url":null,"abstract":"<div><div>Behavioral variant of Frontotemporal Dementia (bvFTD) and Bipolar Disorder (BD) share overlapping symptoms, complicating diagnosis. BvFTD, especially linked to C9orf72 expansions, often mimics BD, highlighting the need for reliable biomarkers. This study aimed to differentiate bvFTD from BD using miRNA profiles in neural-enriched extracellular vesicles (NEVs). A cohort of 100 subjects was analyzed: 40 bvFTD (20 sporadic, 20 C9orf72 carriers), 40 BD, and 20 healthy controls. NEVs were isolated from plasma and profiled using real-time PCR. Among 754 miRNAs, 11 were significantly deregulated in bvFTD and BD. MiR-152-5p was downregulated in sporadic bvFTD, while let-7b, let-7e, miR-18b, and miR-142-5p were altered in C9orf72 carriers. BD patients showed distinct patterns in miR-331-5p, miR-335, and miR-345 compared to bvFTD. Bioinformatics analyses revealed that let-7e, let-7b, miR-18b, and miR-142-5p share common long non-coding RNA (lncRNA) targets, including XIST, NEAT1, and OIP5-AS1, suggesting their involvement in molecular networks relevant to C9orf72-related bvFTD. These miRNA signatures can differentiate bvFTD from BD, especially in C9orf72-related cases, and offer insights into disease pathways. Further research is needed to validate these findings and explore their clinical application.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106867"},"PeriodicalIF":5.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice","authors":"Hila Sapir ,&nbsp;Ghattas Bisharat ,&nbsp;Hava Golan ,&nbsp;Jennifer Resnik","doi":"10.1016/j.nbd.2025.106863","DOIUrl":"10.1016/j.nbd.2025.106863","url":null,"abstract":"<div><div>Folate metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), is crucial for proper neurodevelopment, and disruptions—whether due to genetic polymorphisms or maternal nutritional deficits—have been linked to cognitive and behavioral impairments. Notably, MTHFR-deficient mouse models display altered social interaction and auditory communication, hinting at disruptions in auditory-related circuits and prompting the question of whether impaired folate metabolism might also affect sound processing and perception. Here, using two-photon calcium imaging, we show that MTHFR deficiency increases both spontaneous and sound-evoked activity in the auditory cortex and significantly shifts neuronal response profiles, which in turn elevates perceived loudness while reducing sound-level discrimination. These findings underscore the potential role of compromised folate metabolism in driving the atypical auditory responses and may have broader relevance for understanding sensory dysfunction in various neurodevelopmental conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106863"},"PeriodicalIF":5.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration","authors":"Yifei Zheng ,&nbsp;Jiahui Yang ,&nbsp;Xuanyao Li ,&nbsp;Linjie Qi ,&nbsp;Zhuo Zheng ,&nbsp;Jiming Kong ,&nbsp;Guohui Zhang ,&nbsp;Ying Guo","doi":"10.1016/j.nbd.2025.106862","DOIUrl":"10.1016/j.nbd.2025.106862","url":null,"abstract":"<div><div>Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106862"},"PeriodicalIF":5.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy","authors":"A. Peck ,&nbsp;A. Dadi ,&nbsp;Z. Yavarow ,&nbsp;L.N. Alfano ,&nbsp;D. Anderson ,&nbsp;M.R. Arkin ,&nbsp;T.F. Chou ,&nbsp;E.S. D'Ambrosio ,&nbsp;J. Diaz-Manera ,&nbsp;J.P. Dudley ,&nbsp;A.G. Elder ,&nbsp;N. Ghoshal ,&nbsp;C.E. Hart ,&nbsp;M.M. Hart ,&nbsp;D.M. Huryn ,&nbsp;A.E. Johnson ,&nbsp;K.B. Jones ,&nbsp;V. Kimonis ,&nbsp;E. Kiskinis ,&nbsp;E.B. Lee ,&nbsp;N. Peck","doi":"10.1016/j.nbd.2025.106861","DOIUrl":"10.1016/j.nbd.2025.106861","url":null,"abstract":"<div><div>Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the <em>VCP</em> gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach.</div><div>The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106861"},"PeriodicalIF":5.1,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging animal models to understand non-motor symptoms of Parkinson's disease","authors":"Thomas Wichmann ,&nbsp;Alexandra Nelson ,&nbsp;Eileen Ruth S. Torres ,&nbsp;Per Svenningsson ,&nbsp;Roberta Marongiu","doi":"10.1016/j.nbd.2025.106848","DOIUrl":"10.1016/j.nbd.2025.106848","url":null,"abstract":"<div><div>Parkinson's disease is diagnosed based on motor symptoms, but non-motor symptoms of the disease, such as cognitive impairment, autonomic dysfunction, hyposmia, sleep disorders, and psychiatric disorders heavily impact patient and caregiver quality of life. It has proven challenging to faithfully reproduce and quantify these non-motor phenotypes. Indeed, many non-motor signs in animals that may phenotypically resemble features in patients may be caused by different mechanisms or may not be consistent within the same or similar models. In this review, we survey the existing literature on the assessment of non-motor signs in parkinsonian rodents and non-human primates. We highlight the gaps in our understanding and suggest how researchers might improve experimental designs to produce more meaningful results with the hope of better understanding the disease and developing better therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106848"},"PeriodicalIF":5.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality","authors":"Lara Pizzamiglio ,&nbsp;Fabrizio Capitano ,&nbsp;Evgeniia Rusina ,&nbsp;Giuliana Fossati ,&nbsp;Elisabetta Menna ,&nbsp;Isabelle Léna ,&nbsp;Flavia Antonucci ,&nbsp;Massimo Mantegazza","doi":"10.1016/j.nbd.2025.106853","DOIUrl":"10.1016/j.nbd.2025.106853","url":null,"abstract":"<div><div>Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the <em>SCN1A</em> gene (Na_V1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.</div><div>Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 <em>Scn1a</em>^{<em>+/−</em>} DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of Na_V1.1 expression.</div><div>We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106853"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/− mice","authors":"Mackenzie Smith ,&nbsp;Grace E. Dodis ,&nbsp;Amanda M. Vanderplow ,&nbsp;Sonia Gonzalez ,&nbsp;Yewon Rhee ,&nbsp;Karie Scrogin ,&nbsp;Rocco G. Gogliotti","doi":"10.1016/j.nbd.2025.106859","DOIUrl":"10.1016/j.nbd.2025.106859","url":null,"abstract":"<div><div>Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the <em>methyl-CpG binding protein 2</em> (<em>MeCP2</em>) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M₁ muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M₁ receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M₁ is found on cholinergic interneurons, we hypothesized that M₁-potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, <em>Mecp2</em>^{<em>+/−</em>} and <em>Mecp2</em>^<em>+/+</em> mice were screened for apneas before and after administration of the M₁ positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated <em>Mecp2</em>^{<em>+/−</em>} brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that <em>Mecp2</em>^{<em>+/−</em>} mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M₁ potentiation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106859"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function","authors":"Samuel P. Brown ,&nbsp;Achintya K. Jena ,&nbsp;Joanna J. Osko,&nbsp;Joseph L. Ransdell","doi":"10.1016/j.nbd.2025.106856","DOIUrl":"10.1016/j.nbd.2025.106856","url":null,"abstract":"<div><div>Loss-of-function mutations in tuberous sclerosis 1 (<em>TSC1</em>) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of <em>Tsc1</em> from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific <em>Tsc1</em> deletion (<em>Tsc1</em>^{<em>mut/mut</em>}) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous <em>Tsc1</em> deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to <em>Tsc1</em> haploinsufficiency are delayed compared to age-matched <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons. Together, these data reveal that the loss of <em>Tsc1</em> impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins essential for AIS organization and function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106856"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of efferocytosis in chronic pain —— From molecular perspective","authors":"Hu Zang,&nbsp;Xiaoyu Ji,&nbsp;Wenlong Yao,&nbsp;Li Wan,&nbsp;Chuanhan Zhang,&nbsp;Chang Zhu,&nbsp;Tongtong Liu","doi":"10.1016/j.nbd.2025.106857","DOIUrl":"10.1016/j.nbd.2025.106857","url":null,"abstract":"<div><div>The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106857"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}