Metabolic brain disease最新文献

{"title":"Punica granatum L. peel extract mitigates hyperlipidemia-induced cognitive impairments in zebrafish larvae via modulating LXR signaling.","authors":"Pooja Sharma, Shiv Kumar Saini, Damanpreet Singh","doi":"10.1007/s11011-026-01996-5","DOIUrl":"10.1007/s11011-026-01996-5","url":null,"abstract":"<p><p>Punica granatum L. is known to provide multiple health benefits against several diseased conditions, primarily hyperlipidemia, atherosclerosis, hyperglycemia and cognitive impairments. Many of its health benefits are attributed due to its antioxidant and anti-inflammatory properties. The purpose of the current study was to assess the in vivo effectiveness of an aqueous peel extract of Punica granatum (PuAq) against hyperlipidemia-induced cognitive impairments in a zebrafish larva model. The quantification of major bioactive metabolites of PuAq was done by a high-pressure liquid chromatography technique. The molecular association of the identified metabolites were assessed through in silico docking simulations. The lower confidence limit of the benchmark dose for PuAq in larvae was calculated to be 59.40 µg/mL. Thereafter, larvae at 4 days' post-fertilization were exposed to a 0.1% egg yolk solution with or without PuAq for the subsequent 5 days. Oil Red O staining showed reduced lipid deposition following PuAq treatment. Furthermore, PuAq incubation alleviated hyperlipidemia-induced cognitive decline in larvae subjected to the partition preference test. The extract treatment increased NeuN protein and bdnf expression within the larvae's cephalic region. The treatment modulated the expression of inflammation, oxidative stress, and lipid metabolism-related genes and reduced lipid peroxidation. The protective effects of PuAq were reverted following pre-exposure of GSK2033 (LXR antagonist), which suggested the involvement of LXR receptor activation for the observed changes. In silico docking simulations further supported the molecular interactions between the identified compounds of PuAq and LXR. The study concluded that PuAq protects against hyperlipidemia-induced cognitive impairments in zebrafish larvae.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and redox modulation by 2-deoxy-D-glucose and sodium selenite protects against pentylenetetrazole-kindled seizures, neuroinflammation and cognitive dysfunction.","authors":"Ijaz Alvi, Zohabia Rehman, Muhammad Iftikhar Shoukat, Waseem Ashraf, Syed Muhammad Muneeb Anjum, Fakhir Hannan, Faleh Alqahtani, Imran Imran","doi":"10.1007/s11011-026-01997-4","DOIUrl":"10.1007/s11011-026-01997-4","url":null,"abstract":"<p><p>Cellular metabolism, disrupted brain bioenergetics adaptability and neuroinflammation are inextricably linked in epileptogenesis. Their pathological interplay exacerbates glutamatergic storming, free-radical induced excitotoxicity and glial reactivity leading to network hyperexcitability. Therefore, a novel metabolic approach concurrently targeting cerebral energy metabolism, oxidative stress and neuroinflammation represents a rationale approach for dual seizure control and neuroprotection. 2-deoxy-D-glucose (2DG) inhibits glycolysis while sodium selenite (NaSe) mediates potent anti-inflammatory and anti-oxidant effects. We assumed that the combined intervention would efficiently halt kindling, electroencephalographic ictal activity and associated progression of behavioral comorbidities in PTZ-induced murine model of epilepsy. Furthermore we also evaluated impact of 2DG+NaSe combination on neuroinflammatory markers, oxidative stress markers and histopathological changes in CA1, CA3 and DG subregions of cornu ammonis. Our results demonstrated that combination significantly reduced seizure scores with normalization of aberrant cortical epileptiform discharges and associated quantitative parameters (spike counts, average cyclic height and spiking frequency). This dual approach markedly halted PTZ-induced anxiety-like phenotype and cognitive decline as all animals showed good performance in relevant neurobehavioral assays (OFT, L/D, HBT, T-maze, NOR, and MWM). Mechanistically, combination might have altered glial reactivity and pro-inflammatory cytokines as evidenced by reduced mRNA expression levels of GFAP, IL-1β, and TNF-ɑ. In addition it prompts redox homeostasis (↑ SOD, CAT and GPx enzymatic activity and ↓ MDA levels) and preserved histoarchitecture across cornu ammonis subfields. These outcomes reinforces that concurrent metabolic and oxidative pathways targeting confers robust management of seizure burden and neuroprotection, positioning this combination as a potential multi-modal intervention for patients with DRE.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the role of FGF21 in epilepsy disease: mechanistic insights and therapeutic Potential.","authors":"Gaurav Singh, Khadga Raj Aran","doi":"10.1007/s11011-026-01972-z","DOIUrl":"10.1007/s11011-026-01972-z","url":null,"abstract":"<p><p>Epilepsy, progressive neurological disorder marked repeated seizures, producing aberrant neuronal excitability, followed by oxidative stress, mitochondrial malfunction, and neuroinflammation. Fibroblast growth factor 21 (FGF21), an endocrine member of the FGF family mainly secreted by liver, adipose tissue, and muscle, has turned out to be a potent neuromodulator in addition to its established as lipid and glucose homeostasis. According to studies, FGF21 can cross the Blood-brain barrier (BBB) and provide neuroprotection in experimental models of epilepsy via attenuation of neuronal hyperexcitability, inhibition of inflammation, and mitochondrial preservation. Mechanistically, FGF21 activates the Nrf2 antioxidant pathway, upregulating enzymes like catalase, thereby limiting production of reactive oxygen species. It further improves mitochondrial biogenesis dependent on Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha (PGC-1α) signaling, and suppresses ferroptosis, eventually decreasing susceptibility to seizures. Neuroinflammation is mediated by the downregulation of pro-inflammatory cytokines. Present evidence shows FGF21 administration significantly decreased seizure frequency and severity, underscoring its therapeutic promise. This review focuses on emerging evidence of FGF21's mechanistic actions in disease and its translational relevance novel adjunctive therapeutic strategy, offering opportunities for disease modification beyond conventional anti-seizure drugs.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longxue tongluo capsule enhances ischemic stroke recovery via microbiota-metabolite-gene interactions.","authors":"Guoqing Ren, Wenbo Yang, Jiajia Wang, Jinping Zhang, HuiFang Gao, Xia Gao, Xialin Chen, Tuanjie Wang, Liang Cao, Zhenzhong Wang, Wei Xiao","doi":"10.1007/s11011-026-01976-9","DOIUrl":"10.1007/s11011-026-01976-9","url":null,"abstract":"<p><p>The gut-brain axis represents an emerging therapeutic target. This study seeks to investigate the regulatory effects of LXTL on the brain-gut axis and to elucidate its mechanism of action during the ischemic stroke recovery period. This study investigated the effects of LXTL on a middle cerebral artery occlusion and reperfusion model. The assessment of recovery effects was conducted through the evaluation of brain injury scores, Y-maze performance, open field tests. Furthermore, comprehensive analyses were conducted on the gut microbiota, damaged brain tissue, cecal contents, and brain samples using metagenomic sequencing, transcriptomic sequencing, and non-targeted metabolomics. And the selected targets were verified. Integrated analyses were conducted by constructing correlation networks and performing joint pathway enrichment to elucidate the connections between microbial alterations, metabolite changes, and gene expression modifications. LXTL improved cognitive and exploratory behaviors, reduced brain damage and neuron loss, and enhanced gut health by increasing beneficial bacteria like Eubacterium and Kurthia. It boosted SCFAs, neuroactive metabolites, and altered nucleotide metabolism. LXTL is linked to genes involved in neurorepair and immune homeostasis, correlates with microglial polarization, and is associated with genes such as Ngfr, Card9, Chat, Nkg7, and Gch1 within the pertinent pathways. The integrated network linked LXTL-enhanced microbiota, gut and brain metabolites, and repair genes, facilitating recovery through a neurorepair-immune-metabolic triad. LXTL aids ischemic stroke recovery by altering gut microbiota and gut-brain metabolite profiles, while regulating brain gene networks related to neuroplasticity, inflammation, and metabolism. This demonstrates LXTL's multi-target effects through the gut-brain axis, underscoring the potential of herbal medicine in stroke rehabilitation.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FPR1 drives sepsis-associated cognitive impairment through region-specific transcriptional and splicing dysregulation in the brain.","authors":"Jie Ma, Zhaoyun Wang, Xin Qi, Wendi Li, Junhui Wang, Yanan Huang, Qianqian Ma, Fei Li, Xiaodong Lu, Yuanyuan Fu, Dongmei Yang, Jinlong Yang, Rong Wang, Jun Gao","doi":"10.1007/s11011-026-01994-7","DOIUrl":"10.1007/s11011-026-01994-7","url":null,"abstract":"<p><p>Sepsis-associated encephalopathy (SAE) usually causes long-term cognitive impairment, which seriously compromises the quality of life of patients, but the precise molecular mechanisms have not been elucidated. Formyl peptide receptor 1 (FPR1), a G protein-coupled receptor, plays a pivotal role in systemic and neuroinflammatory responses, but its function in SAE is unclear. Here, we employed Fpr1 knockout mice subjected to cecal ligation puncture (CLP) to model sepsis, integrating behavioral tests, flow cytometry, and transcriptomic and alternative splicing analyses of the hippocampus and prefrontal cortex. Sepsis markedly induced the expansion of reactive myeloid cells and upregulated FPR1 expression. Fpr1 deletion improved cognitive function, attenuated neuroinflammation, enhanced survival, and reversed sepsis-induced downregulation of neuroprotective genes in the hippocampus and myelin-related genes in the prefrontal cortex. Moreover, Fpr1 loss corrected aberrant transcription and splicing events in a brain region-specific manner. Our findings demonstrate that FPR1 drives SAE by orchestrating region-specific transcriptional and splicing networks, providing a rationale for targeting FPR1 to treat post-sepsis cognitive dysfunction.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Castanopsis echinocarpa extract attenuates diabetes-associated peripheral-to-central auditory electrophysiological dysfunction in streptozotocin-induced diabetic mice.","authors":"Sung Woo Shin, Rodrigo Castañeda, Youn Hee Nam, Isabel Rodriguez, Na Woo Kim, Xi Hui Peng, Bin Na Hong, Tong Ho Kang","doi":"10.1007/s11011-026-01995-6","DOIUrl":"10.1007/s11011-026-01995-6","url":null,"abstract":"<p><p>Diabetes-associated auditory dysfunction may extend beyond cochlear threshold elevation and involve broader metabolic and auditory neural abnormalities. This study investigated whether Castanopsis echinocarpa extract (CAE) attenuates peripheral-to-central auditory electrophysiological dysfunction in streptozotocin (STZ)-induced diabetic mice and modulates related auditory and pancreatic stress responses. HEI-OC1 auditory cells were exposed to neomycin or inflammatory cytokines, and Tnf, Il1b, Trpv1, and Gjb2 mRNA expression was analyzed. Post-exposure otic hair cell recovery was assessed in neomycin-treated zebrafish larvae. MIN6 pancreatic β-cells and isolated pancreatic islet cells were used to evaluate oxidative and cytokine-induced β-cell injury. In vivo effects were examined in STZ-induced diabetic mice by measuring fasting blood glucose and auditory brainstem, middle-latency, and late-latency responses. CAE reduced neomycin- and cytokine-induced auditory cell injury, suppressed Tnf, Il1b, and Trpv1 upregulation, and partially restored Gjb2 expression in HEI-OC1 cells. CAE also supported otic hair cell recovery after neomycin injury. In pancreatic models, CAE attenuated H₂O₂- and cytokine-induced β-cell injury and reduced inflammatory gene responses. In STZ-induced diabetic mice, CAE lowered fasting blood glucose and improved ABR threshold shifts as well as AMLR and ALLR latency and amplitude abnormalities. These findings demonstrate concurrent improvements in metabolic and auditory outcomes following CAE treatment in STZ-induced diabetic mice and support further investigation of CAE as a multi-target candidate for diabetes-associated auditory dysfunction.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.","authors":"Sumeyye Yildirim","doi":"10.1007/s11011-026-01998-3","DOIUrl":"10.1007/s11011-026-01998-3","url":null,"abstract":"<p><p>According to the Global Burden of Disease Study 2023, Parkinson's disease (PD) affects an estimated 11.67 million people worldwide, a progressive neurodegenerative condition marked by the accumulation of Lewy bodies containing α-synuclein and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Over the past ten years, advances in genetic and molecular research have shown that PD pathogenesis involves interrelated mechanisms such as impaired protein homeostasis, mitochondrial dysfunction, oxidative stress, defects in lysosomal-autophagic pathways, and chronic neuroinflammation, which go beyond dopaminergic neuronal loss. This review summarizes new data about major genes associated with monogenic and polygenic forms of PD, including SNCA, LRRK2, PRKN, PINK1, DJ-1 (PARK7), GBA1, VPS35, ATP13A2, FBXO7, and the GWAS-prioritized risk genes TMEM175, SCARB2, CTSB, RIT2, DYRK1A, and BAG3, together with the molecular pathways disrupted by these genetic alterations in light of current evidence. The polygenic architecture of PD and ancestry-related variation in genetic risk are also discussed. α-synuclein aggregation and proteostasis networks, oxidative stress, autophagy and mitophagy failure, neuroinflammation, mitochondrial quality control, and epigenetic regulation are all given special attention. Apart from traditional dopaminergic treatments, new therapeutic approaches such as immunotherapies targeting α-synuclein, gene therapies mediated by adeno-associated virus (AAV), induced pluripotent stem cell (iPSC)-based methods, and genotype-guided precision medicine are critically examined. A more comprehensive understanding of the molecular mechanisms underlying PD is expected to facilitate the development of reliable biomarkers and accelerate the clinical translation of disease-modifying therapies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized, placebo-controlled trial of N-acetylcysteine in Parkinson's disease patients: a pilot study.","authors":"Bahar Moasses Ghafari, Aref Rajabi, Parham Geramifar, Asrin Rahimi, Helia Karimi Moghadam, Khaled Rahmani, Arman Rahimmi","doi":"10.1007/s11011-026-01991-w","DOIUrl":"10.1007/s11011-026-01991-w","url":null,"abstract":"<p><p>This pilot trial evaluated the one-year tolerability of oral N-acetylcysteine (NAC) 1200 mg/day in Parkinson's disease (PD) and explored associations with clinical progression, levodopa dose, and striatal dopamine-transporter imaging. Forty-two patients were randomized to NAC or matching placebo twice daily for 12 months in addition to usual care. Completers (n = 32) were assessed at baseline and 12 months with the original UPDRS parts I-IV, 99mTc-TRODAT-1 SPECT, prescribed levodopa dose, and liver/kidney tests. Analyses included paired t-tests, Welch tests of change scores, and linear mixed-effects models with a group × time interaction adjusted for age, sex, and disease duration. No multiplicity correction was applied; results are exploratory. Thirty-two of 42 randomized patients completed both visits. Total UPDRS increased in both groups, but less with NAC than placebo (mean Δ + 5.4 vs. + 9.5 points; difference - 4.1, 95% CI - 7.6 to - 0.5; p = 0.028; mixed-model group × time p = 0.024). Mood-item change also differed (difference - 0.64, 95% CI - 1.17 to - 0.11; p = 0.020). TRODAT binding declined less with NAC (difference in change + 5.5 units, 95% CI 1.7 to 9.3; p = 0.006; group × time p = 0.004). The ≤ 4-year subgroup comprised 9/17 (53%) NAC and 7/15 (47%) placebo participants and showed a similar pattern. Levodopa-dose change was not significant between groups after ANCOVA adjustment for baseline dose, age, sex, and disease duration (adjusted difference - 86 mg/day, 95% CI - 235 to + 64; p = 0.25). Completer laboratory values were stable; discontinuations were not characterized for adverse events. One-year oral NAC was associated with more favorable exploratory clinical and imaging trajectories than placebo. Completer laboratories were unremarkable, but safety cannot be established from completers alone. These data do not establish disease modification and require confirmation in a larger, prospectively powered trial.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral, neuroanatomic, and neuroinflammatory characteristics of metabolic syndrome in cafeteria diet-induced obese male rats.","authors":"Andrej Feješ, Jakub Szabó, Petronela Sušienková, Ladislav Bačiak, Lucia Mihalovičová, Veronika Kunšteková, Veronika Borbélyová, Katarína Šebeková","doi":"10.1007/s11011-026-01989-4","DOIUrl":"10.1007/s11011-026-01989-4","url":null,"abstract":"<p><p>Obesity and metabolic syndrome are associated with low-grade systemic inflammation and neuroinflammation, potentially contributing to structural brain alterations and cognitive decline. This study evaluated brain volumetry, metabolic disturbances, neuroinflammation markers, and behavioral outcomes in a rat model of diet-induced obesity. Male Wistar rats were fed either a standard diet (CTRL; n = 6) or a cafeteria diet (CAF; n = 6) for five months from weaning. Metabolic parameters (weight, glucose tolerance, blood pressure, lipids), behavior (Open Field, Novel Object Recognition), and brain regional volumes (4.7 T MRI) were assessed. Neuroinflammatory markers (tumor necrosis factor-α levels (TNF-α) and glial fibrillary acidic protein (GFAP)) were quantified in the hypothalamus and olfactory bulb. CAF rats developed a metabolic syndrome-like phenotype characterized by abdominal adiposity, insulin resistance, hypertension, and dyslipidemia (p < 0.05). They also showed higher hypothalamic GFAP and TNF-α levels, higher relative orbitofrontal cortex volume (p < 0.05) than controls, whereas lower relative hypothalamic and corpus callosum volumes did not reach significance. Behaviorally, CAF rats exhibited reduced locomotor activity, impaired short-term memory, and higher grooming activity (p < 0.05). Multivariate modeling identified hypothalamic neuroinflammation, severity of continuous metabolic syndrome z-score, and reduced corpus callosum volume as key predictors of cognitive and behavioral impairments. Long-term consumption of a CAF diet induces key features of human metabolic syndrome, hypothalamic neuroinflammation, region-specific brain volumetric alterations, and cognitive deficits. These findings support a role for the metabolic-inflammatory axis in brain vulnerability and suggest that preservation of neuroimmune homeostasis may be important for maintaining cognitive health in obesity-associated metabolic disorders.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers.","authors":"Yingzhen Zhang, Kenhui Wei, Hanxiao Lin, Ziming Guo, Yingtong Lu, Tao Ma","doi":"10.1007/s11011-026-01987-6","DOIUrl":"10.1007/s11011-026-01987-6","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease.</p><p><strong>Results: </strong>The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6.</p><p><strong>Conclusions: </strong>In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}