Neurobiology of Disease最新文献

{"title":"Neurotransmitter-associated structural remodeling of the insula-hippocampus mediates cognitive impairment in age-related hearing loss.","authors":"Yao Wang, Wenqing Li, Wen Ma, Wenjing Zhang, Shuya Wang, Xi Li, Weilong Fu, Bing Liu, Fuxin Ren, Fei Gao, Guangbin Wang","doi":"10.1016/j.nbd.2026.107439","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107439","url":null,"abstract":"<p><p>Age-related hearing loss is a major modifiable risk factor for cognitive decline, yet the dynamic trajectory of brain structural evolution and its underlying neurochemical basis remain poorly understood. This study investigated gray matter (GM) atrophy patterns and their causal relationships in 134 elderly participants, categorized by hearing loss severity, using voxel-based morphometry and causal structural covariance networks (CaSCN). We further explored spatial correlations between these structural changes and neurotransmitter systems using the JuSpace toolbox. Results identified a distinct \"insula-initiated and hippocampus-terminated\" structural atrophy cascade. Bilateral insular atrophy emerged during mild hearing loss and persisted throughout disease progression, while significant hippocampal atrophy primarily appeared in moderate-to-severe stages. CaSCN analysis identified the left insula as a primary \"output hub\" initiating a pathological cascade that converged on the hippocampus as the terminal \"target node\". Critically, the spatial pattern of GM atrophy was significantly coupled with specific neurotransmitter systems, including 5-HT1b, GABAa, and cannabinoid CB1 receptors, particularly in advanced stages. Furthermore, GM volumes of the insula and hippocampus were negatively correlated with high-frequency hearing thresholds and executive dysfunction. These findings reveal an insula-hippocampus axis of structural remodeling in ARHL, offering new insights into the neurobiological mechanisms of cognitive impairment and providing potential imaging biomarkers for early diagnosis.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107439"},"PeriodicalIF":5.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856882","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":"Synaptic attenuation by human alpha-synuclein depends on two amino acids in its C-terminal tail.","authors":"Jen Riba, Liron Samuel, Alexandra Stavsky, Elior Adaoui, Tomer Ashkenazy, Daniel Sevilla-Sanchez, Daniel Gitler","doi":"10.1016/j.nbd.2026.107437","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107437","url":null,"abstract":"<p><p>Alpha-synuclein is a protein primarily expressed in the central and peripheral nervous systems that is firmly implicated in Parkinson's disease and other neurodegenerative diseases termed the synucleinopathies. In post-mortem analyses, macromolecular aggregates of alpha-synuclein are observed in surviving neurons. Consequently, significant research effort has been invested in understanding the properties of alpha-synuclein, with the vast majority focused on the human form. Notwithstanding its high evolutionary conservation, inter-species differences have been noted, and particularly, that while mouse alpha-synuclein fibrillizes in vitro faster than the human form, it is the latter that is more neurotoxic. In light of the synaptic hypothesis of the synucleinopathies, which posits that synaptic dysfunction precedes neurodegeneration, we investigated whether overexpressed human and mouse alpha-synuclein exert distinct effects on neurotransmission. We found that while human alpha-synuclein attenuates synaptic vesicle recycling and disperses the vesicles in synapses of cultured mouse neurons, surprisingly, the mouse protein does not. To explore the basis for these differences, we created chimeric constructs between the two. We report that the two amino acids D121-N122 in the C-terminal tail of human alpha-synuclein are sufficient to discriminate between the distinct synaptic phenotypes of the human and mouse forms, highlighting their functional significance.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107437"},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840765","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":"Reimagining the contribution of iron in Parkinson's disease.","authors":"Rebecka O Serpa, Emily Tufano, James R Connor","doi":"10.1016/j.nbd.2026.107434","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107434","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is the fastest-growing neurodegenerative disease globally, with prevalence increasing more rapidly than Alzheimer's disease. PD pathogenesis has traditionally been framed around iron accumulation in the substantia nigra (SN), resulting in oxidative injury to vulnerable dopaminergic neurons. However, excess iron alone does not readily explain the temporal emergence of dopaminergic susceptibility across the lifespan. Epidemiological and clinical studies consistently show that iron deficiency often precedes PD diagnosis by more than a decade, suggesting that early iron dysregulation establishes a prodromal metabolic state that destabilizes the nigrostriatal system. Here we propose a dynamic two-phase framework in which iron deficiency establishes a latent vulnerability state characterized by impaired iron-dependent enzymatic activity, diminished ferritin buffering, weakened mitochondrial function, and reduced antioxidant defenses. In this primed context, subsequent increases in dopaminergic flux during L-DOPA therapy may amplify oxidative stress by elevating cytosolic dopamine, perturbing iron handling, and promoting dopamine iron redox chemistry that generates quinones and reactive oxygen species (ROS). Transitions in iron availability including iron supplementation, may further aggravate this process but are not required for its initiation. By reframing PD as a disorder shaped by dynamic changes in iron availability interacting with dopaminergic demand, this review integrates evidence across iron biology, dopaminergic signaling, oxidative stress, and neuroinflammation to propose a mechanistically novel model of PD pathogenesis. This conceptual shift highlights new opportunities for risk stratification, biomarker development, and refinement of dopaminergic therapy within iron dysregulated states.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107434"},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840767","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 plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis.","authors":"Gianmaria Senerchia, Valentina Virginia Iuzzolino, Myriam Spisto, Fabiana Panico, Carmela Polito, Lucia Aruta, Mariano Fiorenza, Rosa Sirica, Daniela Terracciano, Raffaele Dubbioso","doi":"10.1016/j.nbd.2026.107430","DOIUrl":"10.1016/j.nbd.2026.107430","url":null,"abstract":"<p><p>Microglial activation contributes to the neuroinflammatory response in amyotrophic lateral sclerosis (ALS). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects microglial activity in several neurodegenerative disorders, but its role in ALS remains unclear. We evaluated plasma sTREM2 as a marker of microglial activation in ALS and compared its diagnostic performance with established blood biomarkers of neurodegeneration. Plasma sTREM2, neurofilament light chain (NfL), phosphorylated tau181 (Ptau181), and glial fibrillary acidic protein (GFAP) were measured in 100 patients with ALS, 30 healthy controls, and 30 disease mimics. Group differences were assessed using general linear models adjusted for age and sex. Associations with clinical variables and inflammatory markers were tested using Spearman correlation, and diagnostic performance was evaluated using receiver operating characteristic curves. Plasma sTREM2 differed across groups (p = 0.016), with higher levels in ALS compared with healthy controls (p = 0.013) and in mimics compared with healthy controls (p = 0.007), but no difference between ALS and mimics (p = 0.394). Discrimination between ALS and healthy controls was modest (area under the curve 0.677), with no discrimination between ALS and mimics (area under the curve 0.512). No association was found between sTREM2 and disease severity or inflammatory markers (all p > 0.10). Plasma sTREM2 increases in ALS but lacks diagnostic specificity and clinical associations, supporting its role as a nonspecific marker of neuroimmune activation rather than a biomarker of disease-related neurodegeneration.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107430"},"PeriodicalIF":5.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818162","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":"Humanized mice carrying a pathogenic GRN deletion as a pre-clinical platform for targeted gene therapies in frontotemporal dementia.","authors":"Benjamin E Life, Pardis Kazemian, Terri L Petkau, Alissandra de Moura Gomes, Sarah B Thomson, Ning Shen, Junia Myung, Farah Jayousi, Tess C Lengyell, Philipp F Lange, Elizabeth M Simpson, Keegan Korthauer, Blair R Leavitt","doi":"10.1016/j.nbd.2026.107419","DOIUrl":"10.1016/j.nbd.2026.107419","url":null,"abstract":"<p><p>Frontotemporal dementia (FTD) is an early onset dementia characterized by neuropathology and changes to patient behaviour. Haploinsufficiency of the gene progranulin (GRN) is a major cause of FTD, for which there are no effective therapies. Corrective gene therapies that restore GRN expression are of clinical interest, but current in vivo systems have limitations. We developed a novel strain of mice expressing a human GRN transgene bearing a four base pair deletion in exon 5 (GRN^{c.388_391delCAGT}) that causes FTD. Characterization of mice expressing the mutant transgene (GRN^mEx5) indicates that GRN^mEx5 is expressed at low levels and retains partial function. The GRN^mEx5 protein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. Following characterization, we sought to determine if mice expressing GRN^mEx5 in the absence of mouse progranulin (Grn^-/-; GRN^mEx5 mice) could enable pre-clinical gene therapy development. Using CRISPR/Cas9 with lipid nanoparticle delivery, we achieved 8.5% correction of GRN^{c.388_391delCAGT} in target cells in Grn^-/-; GRN^mEx5 mice, demonstrating both effective in vivo homology-directed repair and the utility of Grn^-/-; GRN^mEx5 mice for developing novel progranulin-associated FTD therapies. The Grn^-/-; GRN^mEx5 model provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107419"},"PeriodicalIF":5.6,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777081","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":"Blood-based biomarkers of ferroptosis in Parkinson's disease.","authors":"Vincent Huin, Emeline Cailliau, Clément Poupelin, Guillaume Garçon, Mary Dutheil, Ophélie Simonin, Nicolas Beauval, Julien Labreuche, David Blum, Caroline Moreau, Elodie Hainque, Ana Marques, Alexandre Eusebio, Isabelle Benatru, Christine Brefel-Courbon, David Maltete, Caroline Giordana, Melissa Tir, Stéphane Thobois, Jean-Philippe Brandel, Béchir Jarraya, Lucie Hopes, Olivier Rascol, Jean-Christophe Corvol, David Devos, Anne-Sophie Rolland","doi":"10.1016/j.nbd.2026.107414","DOIUrl":"10.1016/j.nbd.2026.107414","url":null,"abstract":"<p><strong>Background: </strong>As Parkinson's disease progresses, patients require second-line treatments such as subthalamic stimulation, the benefits of which may be diminished by the onset of non-dopaminergic axial motor and cognitive disorders. This study aimed to identify blood biomarkers of ferroptosis for predicting the progression of Parkinson's disease at the stage of L-DOPA-related complications.</p><p><strong>Methods: </strong>We analyzed 598 blood samples from patients with PD enrolled in the French multicentric PREDISTIM study. Neurofilament light chain, 4-hydroxy-2-nonenal, glutathione peroxidase activity, ferritin, alpha-synuclein and selenium levels were determined by electrochemiluminescence, ELISA or inductively coupled plasma mass spectrometry. We assessed three single-nucleotide polymorphisms in ACSL4 and GPX4 genes, two key players in ferroptosis. Overall clinical outcomes were evaluated at baseline and one-year post-surgery.</p><p><strong>Results: </strong>At baseline, UPDRS III-Worst OFF was positively correlated with log-4-HNE (p = 0.007). PDQ-39 was negatively correlated with log-ferritin concentration (p = 2.38*10^-4), selenium concentration (p = 0.033) and the rs7887981 in the ACSL4 gene (p = 0.033). Milder cognitive problems were correlated with the rs139736475 in ACSL4 (p = 0.028). One-year post-surgery, change in UPDRS III-Worst OFF was inversely correlated with log-4-HNE levels (p = 0.002).This association remained significant after multivariate analysis and correction for multiple testing.</p><p><strong>Conclusions: </strong>Our results strongly support an association between 4-HNE levels and the progression of motor disability in advanced PD. They also provide multiple lines of evidence favoring a role for ferroptosis in PD progression. Subject to further validation, they could therefore be used to select and stratify patients for future clinical trials.</p><p><strong>Trial registration: </strong>Cohort registered with ClinicalTrials.gov: NCT02360683, on January 2015.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107414"},"PeriodicalIF":5.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777110","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":"DYRK1A and Parkinson's disease, facts and hypotheses.","authors":"Laurent Meijer, Mattias F Lindberg, Gaëlle Hogrel, Bernard Khor","doi":"10.1016/j.nbd.2026.107379","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107379","url":null,"abstract":"<p><p>The dual-specificity, tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is intensively studied because of its implication in numerous human diseases (Down syndrome, Alzheimer's disease, type 2 diabetes, myocardial infarction, various cancers and leukaemia, etc.). Several GWAS studies have identified DYRK1A as a risk factor for Parkinson's disease (PD). DYRK1A indeed phosphorylates at least 20 proteins clearly involved in PD: AMPH, CASP9, DYN1, FOXO, GSK3B, MAP1B, MAPT, MEF2D, NFAT, TP53, PRKN, PLK2, RABs, RCAN1, SEPT4, SNCA, STAT3, SYNJ1, TOM70, WASL. Several other proteins involved in PD interact with DYRK1A: calpains, DSCAM, REST/NRSF, 14-3-3. DYRK1A is involved in axonal transport, neural stem cells proliferation and differentiation, and neuroinflammation. A few DYRK1A inhibitors have been tested on PD models, generally showing protective effects. The overall picture provided by this comprehensive review on the links between DYRK1A and PD advocates for more fundamental studies to understand how DYRK1A participates to the onset and development of PD and dementia with Lewy bodies (DLB), two closely related disorders. It also encourages the evaluation of well-characterized pharmacological modulators of DYRK1A as therapeutic approaches to various aspects of PD and DLB.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107379"},"PeriodicalIF":5.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699271","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":"Glymphatic dysfunction in trigeminal neuralgia: A multimodal MRI study","authors":"Tiantian Chu ,&nbsp;Fei Xiong ,&nbsp;Feng Gao ,&nbsp;Ye Tu","doi":"10.1016/j.nbd.2026.107312","DOIUrl":"10.1016/j.nbd.2026.107312","url":null,"abstract":"<div><h3>Background</h3><div>Trigeminal neuralgia (TN) has traditionally been attributed to peripheral neurovascular compression at the trigeminal nerve root entry zone. Recent evidence, however, suggests central mechanisms may contribute to disease pathogenesis. We investigated whether glymphatic system dysfunction occurs in TN and contributes to its pathophysiology.</div></div><div><h3>Methods</h3><div>This cross-sectional study enrolled 71 patients with classical TN and 52 age-matched healthy controls. All participants underwent comprehensive multimodal MRI assessment, including: (1) diffusion tensor imaging along perivascular spaces (DTI-ALPS) index measurement, (2) free water fraction (FWF) mapping, (3) perivascular space (PVS) burden quantification, and (4) choroid plexus (CP) volumetric analysis using deep learning segmentation to evaluate glymphatic system function.</div></div><div><h3>Results</h3><div>TN patients demonstrated selective glymphatic dysfunction characterized by reduced DTI-ALPS index and increased FWF. Compared to controls, patients showed significantly reduced DTI-ALPS indices (1.34 ± 0.12 vs. 1.41 ± 0.13; <em>p</em> = 0.027) and elevated FWF values (0.34 ± 0.04 vs. 0.32 ± 0.03, <em>p</em> = 0.027), indicating compromised cerebrospinal fluid dynamics. In contrast, structural measures including PVS burden and CP volumes remained comparable between groups (all <em>p</em> &gt; 0.05). Age-related analysis revealed significant correlations with DTI-ALPS decline (ρ = −0.286, <em>p</em> = 0.020) and FWF elevation (ρ = 0.658, <em>p</em> &lt; 0.001), suggesting progressive glymphatic deterioration with aging. However, there is a lack of correlation between glymphatic indicators and pain intensity as well as disease course.</div></div><div><h3>Conclusions</h3><div>These findings indicate that TN is associated with functional impairment of the glymphatic system in the absence of overt perivascular structural abnormalities. This dissociation between functional and structural glymphatic measures challenges conventional neuroimaging paradigms in TN and highlights a previously underrecognized central mechanism.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107312"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156169","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":"Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates","authors":"Roderick P.P.W.M. Maas ,&nbsp;Hector Garcia-Moreno ,&nbsp;Jennifer Faber ,&nbsp;Carlos Gonzalez ,&nbsp;Ludger Schöls ,&nbsp;Jeroen J. de Vries ,&nbsp;Khalaf Bushara ,&nbsp;Kathrin Reetz ,&nbsp;Chiadi U. Onyike ,&nbsp;Heike Jacobi ,&nbsp;Friedrich Erdlenbruch ,&nbsp;Jon Infante ,&nbsp;Magda M. Santana ,&nbsp;Jeannette Hübener-Schmid ,&nbsp;Luís Pereira de Almeida ,&nbsp;Manuela Lima ,&nbsp;Paola Giunti ,&nbsp;Thomas Klockgether ,&nbsp;ESMI study group ,&nbsp;Bart P.C. van de Warrenburg","doi":"10.1016/j.nbd.2026.107301","DOIUrl":"10.1016/j.nbd.2026.107301","url":null,"abstract":"<div><h3>Background</h3><div>Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown.</div></div><div><h3>Objectives</h3><div>To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration.</div></div><div><h3>Methods</h3><div>The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed.</div></div><div><h3>Results</h3><div>MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score &lt; 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters.</div></div><div><h3>Conclusion</h3><div>Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107301"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137796","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":"Impedance-based phenotypic profiling of metabotropic glutamate receptor ligand responses in SCA1 human iPSC-derived neuronal cultures","authors":"Laurie M.C. Kerkhof ,&nbsp;Ronald A.M. Buijsen ,&nbsp;Stefan Hartman ,&nbsp;Barry A. Pepers ,&nbsp;Linda M. van der Graaf ,&nbsp;Jean-Philippe Frimat ,&nbsp;Rongfang Liu ,&nbsp;Laura H. Heitman ,&nbsp;Willeke M.C. van Roon-Mom","doi":"10.1016/j.nbd.2026.107296","DOIUrl":"10.1016/j.nbd.2026.107296","url":null,"abstract":"<div><div>Group 1 metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors (GPCRs) including mGluR1 and mGluR5. These receptors are expressed throughout the central nervous system and play an important role in synaptic plasticity. Dysfunction of mGluR1 in cerebellar Purkinje cells (PC) is observed in spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the <em>ATXN1</em> gene. MGluR1 dysfunction disrupts PC signaling and ultimately contributes to PC death and overall progressive cerebellar dysfunction observed in SCA1. To investigate mGluR1/5 pharmacology in the context of SCA1, mGluR1/5 function was assessed in SCA1 and control human induced pluripotent stem cell (hiPS)cell-derived neuronal cultures using impedance measurements in the xCELLigence real-time cell analyzer (RTCA) system. Culture conditions and protocols for evaluating glutamate receptor activity were first optimized. Subsequently, <em>GRM1</em> and <em>GRM5</em> expression levels were assessed and glutamatergic signaling function was characterized in SCA1 hiPS cell-derived neuronal cultures using both the non-selective endogenous ligand L-glutamate and the selective orthosteric agonist for mGluR1/5, (<em>RS</em>)-3,5-Dihydroxyphenylglycine. To specifically characterize mGluR1 function, mGluR1-specific positive- and negative allosteric modulators (Ro0711401 and JNJ16259685 respectively) were tested. Results showed reduced mGluR1 and decreased mGluR5 RNA expression levels and diminished mGluR1/5 responses in the SCA1 hiPS cell-derived neuronal cultures. These results underline the potential utility of impedance measurements for characterizing GPCR function and pharmacological testing in a high-throughput manner in patient-derived neuronal cultures.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107296"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080745","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}