Neurobiology of Disease最新文献

{"title":"Association between plasma glucosylsphingosine levels and dyskinesia burden in GBA1-related Parkinson's disease","authors":"Massimo Marano ,&nbsp;Carmela Zizzo ,&nbsp;Francesco Cavallieri ,&nbsp;Micol Avenali ,&nbsp;Tommaso Schirinzi ,&nbsp;Edoardo Monfrini ,&nbsp;Francesca Spagnolo ,&nbsp;Rosa De Micco ,&nbsp;Silvia Ramat ,&nbsp;Maria Chiara Malaguti ,&nbsp;Federico Reali ,&nbsp;Roberto Cilia ,&nbsp;Miryam Carecchio ,&nbsp;Andrea Pilotto ,&nbsp;Roberto Erro ,&nbsp;Ilaria Antonella di Vico ,&nbsp;Mario Meloni ,&nbsp;Giulia Di Lazzaro ,&nbsp;Sara Pietracupa ,&nbsp;Claudia Ledda ,&nbsp;Alessio Di Fonzo","doi":"10.1016/j.nbd.2026.107271","DOIUrl":"10.1016/j.nbd.2026.107271","url":null,"abstract":"<div><h3>Background</h3><div><em>GBA1</em> mutation is the most significant genetic risk factor for Parkinson's disease (PD). It encodes glucocerebrosidase (GCase), whose dysfunction – seen in Gaucher disease - leads to the accumulation of glucosylceramide and its derivate glucosylsphingosine (GlcSph). However, it remains unclear whether GCase and GlcSph are relevant in PD patients carrying no or monoallelic <em>GBA1</em> variants, and what their clinical impact might be.</div></div><div><h3>Objective</h3><div>Investigating the relationships between <em>GBA1</em> mutations, GCase, GlcSph, and clinical features in a large PD cohort.</div></div><div><h3>Methods</h3><div>We performed a cross-sectional study of PD patients screened for <em>GBA1</em> mutations, GCase activity, and GlcSph via dried blood spot tests. Patients were classified as heterozygous mutation carriers (<em>GBA1</em>-PD) or non-carriers (non<em>GBA1</em>-PD). Collected data included motor and non-motor parameters. Molecular and clinical differences were compared between <em>GBA1</em>-PD and non<em>GBA1</em>-PD. Distinctive clinical features were further investigated through multivariate models to test their correlations with biochemical data.</div></div><div><h3>Results</h3><div>The cohort included 611 subjects (225 <em>GBA1</em>-PD, 386 non<em>GBA1-</em>PD). <em>GBA1</em>-PD presented earlier onset, lower cognitive scores, higher incidence of mood disturbances and more advanced stage. Motor assessment revealed a higher frequency and severity of dyskinesias, independently from disease duration and LEDD. GlcSph levels showed an independent correlation with dyskinesia severity and time at onset in <em>GBA1</em>-PD patients, which was independent of sex, LEDD, UPDRS-III, disease duration and <em>GBA1</em> mutation class.</div></div><div><h3>Conclusions</h3><div>This study reveals an association between GlcSph and dyskinesias in <em>GBA1</em>-PD, that should prompt further investigation to assess the GlcSph role as a possible biomarker and target to tackle dyskinesias in <em>GBA1</em>-PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107271"},"PeriodicalIF":5.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990025","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":"Afferent-driven modulation of spinal interneurofn circuits across disease stages in amyotrophic lateral sclerosis","authors":"Sina Sangari ,&nbsp;Alexandra Lackmy-Vallée ,&nbsp;Iseline Peyre ,&nbsp;Pierre-François Pradat ,&nbsp;Véronique Marchand-Pauvert","doi":"10.1016/j.nbd.2026.107270","DOIUrl":"10.1016/j.nbd.2026.107270","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively disrupts voluntary motor command through combined cortical and spinal motor neuron degeneration. However, how spinal circuits reorganize during the disease remains poorly understood, particularly in humans. This study examined the function of excitatory and inhibitory spinal interneuron circuits that control upper and lower limb movements, using non-invasive electrophysiological techniques targeting specific afferent–motoneuron pathways at cervical and lumbar levels. These segments are clinically relevant, as spinal-onset forms constitute the predominant clinical presentation of ALS. We compared patients with ALS at different stages of functional impairment to healthy individuals. Spinal circuits predominantly driven by muscle spindle afferents (group Ia and II) showed, at the group level, a marked reduction in inhibition together with enhanced propriospinal excitation. In contrast, pathways mediated by tendon afferents (group Ib) and cutaneous inputs appeared preserved in unstratified analyses. However, when accounting for disease stage, inhibitory dysfunction emerged as an early feature, whereas excitation increased progressively with functional impairment, and modulations also became detectable in Ib- and cutaneous-driven responses. These findings reveal an afferent- and stage-dependent hierarchy of spinal dysfunction, following a reproducible sequence from early disinhibition to maladaptive excitation. This dynamic pattern mirrors the organization observed in preclinical spinal models and aligns with cortical pathophysiology, where widespread loss of inhibition precedes selective increases in excitation. Together, these results refine the mechanistic understanding of motor network disorganization in ALS and identify inhibitory interneurons as potential therapeutic targets to stabilize spinal network function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107270"},"PeriodicalIF":5.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979243","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":"Elevated neurotransmitter levels in people with HIV are associated with attention function","authors":"Ilenia Salsano ,&nbsp;Jason A. John ,&nbsp;Ryan J. Glesinger ,&nbsp;Grant M. Garrison ,&nbsp;Kennedy A. Kress ,&nbsp;Aubrie J. Petts ,&nbsp;Danielle L. Rice ,&nbsp;Grace C. Ende ,&nbsp;Lucy K. Horne ,&nbsp;Anna T. Coutant ,&nbsp;Pamela E. May-Weeks ,&nbsp;Georg Oeltzschner ,&nbsp;Tony W. Wilson","doi":"10.1016/j.nbd.2026.107273","DOIUrl":"10.1016/j.nbd.2026.107273","url":null,"abstract":"<div><div>People with HIV (PWH) often exhibit cognitive impairments, particularly in attention and executive function domains, despite effective viral suppression. The neurophysiological and neurochemical mechanisms underlying these deficits remain poorly understood. Herein, we used proton magnetic resonance spectroscopy (¹H-MRS) at 3 T with spectral editing to quantify the inhibitory (GABA+: GABA and co-edited macromolecules) and excitatory (Glx: glutamate and glutamine) neurotransmitter pools in the calcarine cortex of 27 virally suppressed PWH and 27 age- and sex-matched controls. We also estimated several secondary metabolites commonly implicated in neuroinflammatory and energetic processes, including total <em>N</em>-acetylaspartate (tNAA), total choline (tCho), total creatine (tCr), and myo-inositol (mI). Following best practices, metabolite concentrations were scaled to the unsuppressed water signal and corrected for voxel tissue composition, including gray matter, white matter, and CSF percentages. Compared with controls, PWH exhibited significantly elevated GABA+, Glx, and mI levels, suggesting parallel alterations in inhibitory, excitatory, and glial pathways. Notably, higher Glx levels were associated with longer HIV disease duration and increases in Glx and mI were coupled to decreases in attentional performance, linking neurochemical alterations to both disease progression and cognitive dysfunction. In sum, these findings provide the first evidence of concurrent GABA+ and Glx alterations in virally suppressed PWH, supporting a model in which disrupted excitatory-inhibitory balance contributes to cortical instability and attentional deficits in HIV.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107273"},"PeriodicalIF":5.6,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966798","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":"2026-01-10","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":"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":"2026-01-10","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":"HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs","authors":"Derk Draper ,&nbsp;Anna E. George ,&nbsp;Tineke Veenendaal ,&nbsp;Suzanne van Dijk ,&nbsp;Elly Z. Soltani ,&nbsp;Paolo Sanzà ,&nbsp;Frederik J. Verweij ,&nbsp;Judith Klumperman ,&nbsp;Ginny G. Farías","doi":"10.1016/j.nbd.2026.107269","DOIUrl":"10.1016/j.nbd.2026.107269","url":null,"abstract":"<div><div>Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic Aβ that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the <em>endo</em>-lysosomal system, but the molecular mechanisms that coordinate these processes remain not fully understood. Here, we studied the HOPS complex, a central regulator of <em>endo</em>-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the γ-secretase subunit PSEN2. However, they do contain BACE1, which contributes to the build-up of toxic APP C-terminal fragments (APP-CTFs). Notably, loss of HOPS function enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS loss-of-function and aberrant APP processing, with implications for neurodegeneration.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107269"},"PeriodicalIF":5.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960012","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 C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide","authors":"Vaishnavi Nagarajan ,&nbsp;Caitlin L. Libowitz ,&nbsp;Brian D. Ackley ,&nbsp;Michael S. Wolfe","doi":"10.1016/j.nbd.2026.107267","DOIUrl":"10.1016/j.nbd.2026.107267","url":null,"abstract":"<div><div>The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ∼150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38–43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin—the catalytic component of γ-secretase—cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to Aβ peptides, apparently through stabilization of γ-secretase enzyme-substrate (<em>E</em>-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new <em>C. elegans</em> models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to Aβ in vivo<em>.</em> We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable <em>E</em>-S complex formation without Aβ42 or Aβ production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another γ-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled γ-secretase <em>E</em>-S complexes in the absence of Aβ production and not by simple loss of proteolytic function. This new <em>C. elegans</em> system provides a powerful platform to study the role of dysfunctional γ-secretase substrate processing in FAD pathogenesis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107267"},"PeriodicalIF":5.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959906","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":"Ultra-high-field (9.4 T) ex vivo diffusion MRI tractography reveals microstructural differences in Parkinson's disease motor subtypes","authors":"Jackson Boonstra ,&nbsp;Stijn Michielse ,&nbsp;Yasin Temel ,&nbsp;Ali Jahanshahi ,&nbsp;Alard Roebroeck","doi":"10.1016/j.nbd.2026.107266","DOIUrl":"10.1016/j.nbd.2026.107266","url":null,"abstract":"<div><div>The structural correlates of Parkinson's disease (PD) with tremor-dominance and those with non-tremor dominance are not fully differentiated. Ultra-high field magnetic resonance imaging (UHF-MRI) allows the human brain to be imaged at a higher resolution compared to traditional scanner strengths but has largely been underutilized in PD research. Scanning post-mortem tissue allows for increased scan times and fewer movement issues leading to improved image quality, especially higher spatial resolution. We performed diffusion MRI on twelve post-mortem hemispheres (eight parkinsonian (four tremor-dominant, four non-tremor-dominant) and four non-demented controls) scanned with a specialized 9.4 Tesla human post-mortem brain coil. Diffusion tensor analysis was performed for local scalar diffusion metrics and constrained spherical deconvolution tractography was performed for global connectivity metrics. Compared to both non-tremor-dominant patients and controls, tremor-dominant patients displayed greater hemispheric fractional anisotropy. While motor subtypes were similar to each other across multiple regional diffusion metrics, each subtype demonstrated subtype-specific differences when compared to controls. Interconnections within basal ganglia circuitry mainly involving the internal capsule showed disparities across both subtypes and controls. Our findings show motor subtype specific circuitopathies in PD and improve the mapping of connectivity fingerprints potentially relevant in the planning of treatment regimes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107266"},"PeriodicalIF":5.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952613","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":"Hyperactivity, compulsive-like behaviours, and impaired flexibility in mouse models of Duchenne muscular dystrophy","authors":"Faouzi Zarrouki ,&nbsp;Léa Ceschi ,&nbsp;Rubén Miranda ,&nbsp;Amel Saoudi ,&nbsp;Cyrille Vaillend","doi":"10.1016/j.nbd.2026.107265","DOIUrl":"10.1016/j.nbd.2026.107265","url":null,"abstract":"<div><div>X-linked Duchenne muscular dystrophy (DMD), caused by mutations in a gene coding several dystrophin isoforms from independent promoters, is associated with a range of brain-related comorbidities. Intellectual disability is variably expressed depending on the position of the genetic variants, intelligence quotients being negatively correlated with the number of deficient brain dystrophins. However, the genetic basis of other phenotypes underlying cognitive deficits and neuropsychiatric disorders, such as executive dysfunctions and attention deficit/hyperactivity disorder (ADHD), is still unclear. In this study, we behaviourally characterized two mouse models (<em>mdx</em>^{<em>5Cv</em>,} <em>mdx52</em>) lacking brain dystrophins, Dp427 or Dp427 and Dp140 respectively, which together correspond to about 90% of DMD patients' mutation profiles. We included new paradigms allowing automated, high-throughput, collection of behavioural data from social groups of mice in home-cage conditions. We show that both models display unaltered circadian exploratory activity in such conditions, opposite of the motor inhibition expressed in stand-alone behavioural tests. In contrast, both models variably developed hyperactivity, impulsive and perseverative behaviours, triggered by sudden task-condition changes such as increases in waiting delays to access rewards, with a moderate impact on delay discounting. Cumulative Dp427 and Dp140 deficiency resulted in reduced memory of fear extinction and impaired behavioural flexibility during reversal of the learning-strategy rule in a working-memory task. These results are relevant to the comorbid diagnosis of ADHD across main mutation profiles in DMD; they also highlight a specific contribution of Dp140 deficiency to maladaptive behavioural inflexibility, and provide new genotype-specific outcome measures to probe brain-targeting treatments in future preclinical studies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107265"},"PeriodicalIF":5.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952601","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":"2026-01-06","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}