Neurobiology of Disease最新文献

{"title":"Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease","authors":"Filip Fredlund ,&nbsp;Claes Fryklund ,&nbsp;Olivia Trujeque-Ramos ,&nbsp;Hannah A. Staley ,&nbsp;Joaquin Pardo ,&nbsp;Kelvin C. Luk ,&nbsp;Malú G. Tansey ,&nbsp;Maria Swanberg","doi":"10.1016/j.nbd.2025.106841","DOIUrl":"10.1016/j.nbd.2025.106841","url":null,"abstract":"<div><div>Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observed up to 70 % loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106841"},"PeriodicalIF":5.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425878","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":"Long-term exposure to anti-GluA3 antibodies triggers functional and structural changes in hippocampal neurons","authors":"Maria Italia ,&nbsp;Alessio Spinola ,&nbsp;Barbara Borroni ,&nbsp;Monica DiLuca ,&nbsp;Fabrizio Gardoni","doi":"10.1016/j.nbd.2025.106843","DOIUrl":"10.1016/j.nbd.2025.106843","url":null,"abstract":"<div><div>Autoantibodies targeting the GluA3 subunit of AMPA receptors (AMPARs) are implicated in various neurological disorders, including Rasmussen's encephalitis, epilepsy, and frontotemporal dementia. However, their precise role in disease pathology remains insufficiently understood. This study investigated the long-term effects of human anti-GluA3 antibodies (anti-GluA3 hIgGs) on neuronal morphology and function using primary rat hippocampal neurons. We found that long-term exposure to anti-GluA3 hIgGs leads to the delocalisation of GluA3-containing AMPARs at extrasynaptic sites. This molecular event is correlated to dendritic arbor reorganisation, characterised by increased complexity near the soma and progressive simplification in distal regions as well as an increase in the number of shorter dendrites and a corresponding loss of longer ones, thus suggesting altered dendritic pruning dynamics. The altered neuronal architecture was accompanied by an increase in the number of dendritic spines and a modification of their morphology, indicating relevant changes in synaptic connectivity. Functionally, anti-GluA3 hIgGs significantly enhanced NMDA receptor-mediated postsynaptic Ca²⁺ currents and increased nuclear levels of phosphorylated cAMP response element-binding protein (CREB), indicating altered signal transduction. Overall, our study provides critical insights into the role of anti-GluA3 hIgGs in disease and potentially identifies new therapeutic targets for pathological conditions where they are present.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106843"},"PeriodicalIF":5.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425881","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":"The impact of gut microbiota on the occurrence, treatment, and prognosis of ischemic stroke","authors":"Liying Chen ,&nbsp;Xi Wang ,&nbsp;Shiqi Wang ,&nbsp;Weili Liu ,&nbsp;Zhangyong Song ,&nbsp;Huiling Liao","doi":"10.1016/j.nbd.2025.106836","DOIUrl":"10.1016/j.nbd.2025.106836","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a cerebrovascular disease that predominantly affects middle-aged and elderly populations, exhibiting high mortality and disability rates. At present, the incidence of IS is increasing annually, with a notable trend towards younger affected individuals. Recent discoveries concerning the “gut-brain axis” have established a connection between the gut and the brain. Numerous studies have revealed that intestinal microbes play a crucial role in the onset, progression, and outcomes of IS. They are involved in the entire pathophysiological process of IS through mechanisms such as chronic inflammation, neural regulation, and metabolic processes. Although numerous studies have explored the relationship between IS and intestinal microbiota, comprehensive analyses of specific microbiota is relatively scarce. Therefore, this paper provides an overview of the typical changes in gut microbiota following IS and investigates the role of specific microorganisms in this context. Additionally, it presents a comprehensive analysis of post-stroke microbiological therapy and the relationship between IS and diet. The aim is to identify potential microbial targets for therapeutic intervention, as well as to highlight the benefits of microbiological therapies and the significance of dietary management. Overall, this paper seeks to provide key strategies for the treatment and management of IS, advocating for healthy diets and health programs for individuals. Meanwhile, it may offer a new perspective on the future interdisciplinary development of neurology, microbiology and nutrition.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106836"},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425882","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":"Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline","authors":"Noelia Granado ,&nbsp;Liliana Mendieta ,&nbsp;Yousef Tizabi ,&nbsp;Mario Gustavo Murer ,&nbsp;Rosario Moratalla","doi":"10.1016/j.nbd.2025.106839","DOIUrl":"10.1016/j.nbd.2025.106839","url":null,"abstract":"<div><div>Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson's disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106839"},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414222","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":"GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus","authors":"Minjia Xie ,&nbsp;Xin Wu ,&nbsp;Xi Liu ,&nbsp;Longyuan Li,&nbsp;Feng Gu,&nbsp;Xinyu Tao,&nbsp;Bingyi Song,&nbsp;Lei Bai,&nbsp;Di Li,&nbsp;Haitao Shen,&nbsp;Zongqi Wang,&nbsp;Wei Gao","doi":"10.1016/j.nbd.2025.106838","DOIUrl":"10.1016/j.nbd.2025.106838","url":null,"abstract":"<div><h3>Background</h3><div>Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded protein response (UPRmt) and its potential protective effects on hippocampal neurons following experimental status epilepticus (SE).</div></div><div><h3>Methods</h3><div>The effects of GrpEL1 were assessed <em>in vivo</em> using a Lithium-pilocarpine rat model of SE and <em>in vitro</em> with glutamate-treated HT22 hippocampal cells. Protein expression and interactions were analyzed by Western blot, immunofluorescence, and co-immunoprecipitation. Neuronal survival was evaluated through Nissl staining. Mitochondrial function was evaluated aggresome formation, mitochondrial membrane potential (MMP) assays, mitochondrial oxygen consumption rate (OCR) measurements, and behavioral assessments using the Morris water maze.</div></div><div><h3>Results</h3><div>In the SE rat model, mtHSP70 levels were significantly upregulated in mitochondria, while GrpEL1 expression remained relatively stable. Overexpression of GrpEL1 led to a reduction in neuronal damage and improved functional recovery post-SE. <em>In vitro</em>, GrpEL1 overexpression enhanced the GrpEL1-mtHSP70 interaction, reduced the accumulation of misfolded proteins, and decreased neuronal apoptosis. Furthermore, GrpEL1 overexpression mitigated mitochondrial dysfunction by preserving MMP and improving mitochondrial bioenergetics, as evidenced by enhanced mitochondrial OCR.</div></div><div><h3>Conclusion</h3><div>GrpEL1 plays a crucial role in maintaining mitochondrial proteostasis and mitigating hippocampal neuronal injury following SE by regulating UPRmt. These findings suggest that GrpEL1 may represent a promising target for therapeutic intervention to protect against seizure-induced neurodegeneration.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106838"},"PeriodicalIF":5.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388313","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":"Impairment in the homeostatic recruitment of layer 5/6 neurons following whisker stimulation in Fmr1 KO mice","authors":"Alishah Lakhani ,&nbsp;Washington Huang ,&nbsp;Chris C. Rodgers ,&nbsp;Peter Wenner","doi":"10.1016/j.nbd.2025.106837","DOIUrl":"10.1016/j.nbd.2025.106837","url":null,"abstract":"<div><div>Mouse models of Fragile X Syndrome (FXS) have demonstrated impairments in sensory-evoked neuronal firing of excitatory and inhibitory neurons. Homeostatic plasticity does not compensate for these changes in activity. Previous work has shown that impairments in homeostatic plasticity mechanisms are observed in FXS, including deficits in synaptic scaling and intrinsic excitability. Here, we aimed to examine how sensory integration changes in vivo following a homeostatic perturbation, unilateral whisker deprivation (WD), in an <em>Fmr1</em> knock out (KO) mouse model. We used multi-electrode array recordings of neurons in the lightly anesthetized juvenile mouse somatosensory cortex, and found that whisker-evoked responses in layer 5/6 (L5/6) excitatory neurons were weaker in the KO compared to the wild-type (WT). We show that WD in the WT leads to a compensatory increase in the proportion of L5/6 somatosensory neurons that were recruited following whisker stimulation, but this did not occur in the KO. On the other hand, certain compensatory responses were observed in the KO following WD; the firing rate of the whisker-responsive neurons was increased following both a 2- and 7-day WD. Similar to excitatory neurons, we observed increased recruitment of fast spiking (presumed inhibitory) neurons following WD in the WT, but not KO. Our results suggest that certain homeostatic mechanisms are impaired in the KO, while others appear to remain intact. Compromised homeostatic plasticity in development could influence adult sensory processing and long-term cortical organization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106837"},"PeriodicalIF":5.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409336","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":"Joint analysis of single-cell RNA sequencing and bulk transcriptome reveals the heterogeneity of the urea cycle of astrocytes in glioblastoma","authors":"Minfeng Tong ,&nbsp;Qi Tu ,&nbsp;Lude Wang ,&nbsp;Huahui Chen ,&nbsp;Xing Wan ,&nbsp;Zhijian Xu","doi":"10.1016/j.nbd.2025.106835","DOIUrl":"10.1016/j.nbd.2025.106835","url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma (GB) is incurable with a dismal prognosis. Single-cell RNA sequencing (scRNA-seq) is a pivotal tool for studying tumor heterogeneity. The dysregulation of the urea cycle (UC) frequently occurs in tumors, but its characteristics in GB have not been illuminated. This study integrated scRNA-seq UC scores and bulk RNA-seq data to build a GB prognostic model.</div></div><div><h3>Methods</h3><div>Samples from 3 pairs of GB patients were collected for scRNA-seq analysis. GB-mRNA expression data, clinical data, and SNV mutation data were sourced from the Cancer Genome Atlas (TCGA). GB-mRNA expression data and clinical data were downloaded from the Chinese Glioma Genome Atlas (CGGA). GB RNA-seq data and clinical data were obtained from Gene Expression Omnibus (GEO) database. The R package <em>Seurat</em> was applied for scRNA-seq data processing. UMAP and TSNE were used for dimensionality reduction. UCell enrichment method was employed to score each astrocyte. Monocle algorithm was applied for pseudotime trajectory analysis. <em>CellChat</em> R package was applied for cell communication analysis. Cell labeling was performed on the results of the nine subclusters of astrocytes. The GSE138794 dataset was used to validate the results of single-cell classification. For bulk RNA-seq, univariate Cox and LASSO analyses were undertaken to screen prognostic genes, while multivariate Cox regression analysis was applied to set up a prognostic model. The differences between high-risk (HR) and low-risk (LR) groups were studied in terms of immune infiltration, sensitivity to anti-tumor drugs, <em>etc.</em> We verified the effect of the marker gene on the function of GB cells at the cellular level.</div></div><div><h3>Results</h3><div>The analysis of scRNA-seq data yielded 7 core cell types. Further clustering of the largest proportion of astrocytes resulted in 9 subclusters. UC score and pseudotime analysis revealed the heterogeneity and differentiation process among subclusters. Subcluster 8 was annotated as an immature astrocyte (marker: CXCL8), and this cell cluster had a higher UC score. The results were validated in the GSE138794 dataset. Combining UC scores, we performed univariate Cox and LASSO to select prognostic genes on bulk RNA-seq data. A prognostic model based on 5 feature genes (RGS4, CTSB, SERPINE2, ID1, and CALD1) was established through multivariate Cox analysis. In addition, patients in the HR group had higher immune infiltration and immune function. Final cell experiments demonstrated that 5 feature genes were highly expressed in GB cells. CALD1 promoted the malignant phenotype of GB cells.</div></div><div><h3>Conclusion</h3><div>We set up a novel prognostic model for predicting the survival of GB patients by integrating bulk RNA-seq and scRNA-seq data. The risk score was closely correlated with immune infiltration and drug sensitivity, pinpointing it as a promising independent prognostic factor.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106835"},"PeriodicalIF":5.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409351","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":"Microglia TRPC1 SUMOylation drives neuroinflammation after stroke by modulating NLRP3 activity via increasing TRPC1 interaction with ARRB2","authors":"Huinan Zhang ,&nbsp;Xinzhe Du ,&nbsp;Tian Gao ,&nbsp;Xing Wang ,&nbsp;Huifeng Zhang ,&nbsp;Manyang Yu ,&nbsp;Jing Huang","doi":"10.1016/j.nbd.2025.106833","DOIUrl":"10.1016/j.nbd.2025.106833","url":null,"abstract":"<div><div>Microglial canonical transient receptor potential channel 1 (TRPC1) has been proposed to influence neuroinflammation after cerebral ischemia and reperfusion injury (CIRI), however, the underlying mechanism remains poorly understood. This study demonstrates that TRPC1 is modified by small ubiquitin-related modifier (SUMO)ylation. Our findings suggest a notable increase in microglial TRPC1 SUMOylation within both the middle cerebral artery occlusion reperfusion (MCAO/R) model and the in vitro oxygen-glucose deprivation/regeneration model. Mice with a loss of TRPC1 SUMOylation in microglia exhibited improved stroke outcomes including reduced behavior deficits, infarct volume, blood brain barrier damage as well as neuronal apoptosis. Mechanistically, SUMOylation of microglial TRPC1 exacerbated neutrophil infiltration into the peri-infarct area. Additionally, SUMOylated TRPC1 activates the Nod-like receptor protein (NLRP) 3 signaling pathway in microglia and stimulates multiple CC-chemokine ligands and C-X-C motif ligand chemokines after MCAO/R. SUMOylated TRPC1 facilitates the interaction between TRPC1 and β-arrestin2 (ARRB2), a negative regulator of NLRP3 inflammasome, which disrupts the NLPR3/ARRB2 complex and stimulates the activation of the NLPR3 signaling pathway. Furthermore, ARRB2 directly binds to the residues 46 to 61 of TRPC1 N terminus, which is enhanced by TRPC1 SUMOylation. Collectively, our findings demonstrate a previously unidentified mechanism by which SUMOylated TRPC1 in microglia regulates leukocyte infiltration after stroke, suggesting that the inhibition of microglial TRPC1 SUMOylation may provide therapeutic benefits for CIRI.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106833"},"PeriodicalIF":5.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372691","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":"Insights into dentatorubral-pallidoluysian atrophy from a new Drosophila model of disease","authors":"Matthew V. Prifti ,&nbsp;Oluwademilade Nuga ,&nbsp;Ryan O. Dulay ,&nbsp;Nikhil C. Patel ,&nbsp;Truman Kula ,&nbsp;Kozeta Libohova ,&nbsp;Autumn Jackson-Butler ,&nbsp;Wei-Ling Tsou ,&nbsp;Kristin Richardson ,&nbsp;Sokol V. Todi","doi":"10.1016/j.nbd.2025.106834","DOIUrl":"10.1016/j.nbd.2025.106834","url":null,"abstract":"<div><div>Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disorder that presents with ataxia, dementia and epilepsy. As a member of the polyglutamine family of diseases, DRPLA is caused by abnormal CAG triplet expansion beyond 48 repeats in the protein-coding region of <em>ATROPHIN 1</em> (<em>ATN1</em>), a transcriptional co-repressor. To better understand DRPLA, we generated new <em>Drosophila</em> lines that can be induced to express full-length, human ATN1 with a normal (Q7) or pathogenic (Q88) repeat in a variety of cells, including neuronal, glial or any other type of tissue. Expression of ATN1 is toxic, with the polyglutamine-expanded version being consistently more problematic than wild-type ATN1. Fly motility, longevity and internal structures are negatively impacted by pathogenic ATN1. RNA-seq identified altered protein quality control and immune pathways in the presence of pathogenic ATN1. Based on these data, we conducted genetic experiments that confirmed the role of protein quality control components that ameliorate or exacerbate ATN1 toxicity. Hsc70–3, a chaperone, arose as a likely suppressor of toxicity. VCP (a proteasome-related AAA ATPase), Rpn11 (a proteasome-related deubiquitinase) and select DnaJ proteins (co-chaperones) were inconsistently protective, depending on the tissues where they were expressed. Lastly, informed by RNA-seq data that exercise-related genes may also be involved in this model of DRPLA, we conducted short-term exercise, which improved overall fly motility. This new model of DRPLA will prove important to understanding this understudied disease and will help to identify therapeutic targets for it.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106834"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374478","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":"Effects of trace element dysregulation on brain structure and function in spinocerebellar Ataxia type 3","authors":"LiHua Deng ,&nbsp;Liu Feng ,&nbsp;JingWen Li ,&nbsp;YongHua Huang ,&nbsp;PeiLing Ou ,&nbsp;LinFeng Shi ,&nbsp;Hui Chen ,&nbsp;YuHan Zhang ,&nbsp;LiMeng Dai ,&nbsp;Yuan He ,&nbsp;Chen Wei ,&nbsp;HuaFu Chen ,&nbsp;Jian Wang ,&nbsp;Leinian Li ,&nbsp;Chen Liu","doi":"10.1016/j.nbd.2025.106816","DOIUrl":"10.1016/j.nbd.2025.106816","url":null,"abstract":"<div><div>Spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder caused by excess CAG repeats in the <em>ATXN3</em> gene, leads to progressive cerebellar ataxia and other symptoms. The results of previous studies suggest that trace element dysregulation contributes to neurodegenerative disorder onset. Here, we investigated the relationships of trace element dysregulation with CAG repeat length, clinical severity, and brain structural and functional connectivity in 45 patients with SCA3 and 44 healthy controls (HCs). Blood levels of lithium (Li), selenium (Se), and copper (Cu) were significantly lower in patients with SCA3 than in HCs; Li and Se levels were negatively correlated with CAG repeat length, especially in the manifest subgroup. Diffusion tensor imaging combined with resting-state functional magnetic resonance imaging revealed that Li levels were negatively correlated with fractional anisotropy in the white matter (WM) of bilateral frontal and parietal regions; tractography mapping showed disorder structural connectivity of Li-associated region nerve fiber pathways in patients with SCA3. Dynamic causal modeling analyses showed bidirectional causal connectivity from the inferior parietal lobule(IPL) to the cerebellum was significantly correlated with the blood level of Li in patients with SCA3. Time series correlation-based functional connectivity analysis revealed that the intrinsic connectivities of the bilateral dorsal premotor cortex(PMd) and IPL with local cerebellar regions were significantly weaker in patients with SCA3 than in HCs. Our results suggest that trace element dysregulation, especially Li deficiency, induces brain alterations and clinical manifestations in patients with SCA3; Li supplementation may be beneficial for WM or astrocytes in this patient population.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106816"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374463","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}