Pain is a prominent non-motor symptom of Parkinson's disease (PD); it may appear in various levels (elevated or diminished) during waking hours and substantially reduces quality of life. Although subthalamic nucleus (STN) signal analysis has dramatically advanced our comprehension of PD, the roles of bilateral STN, the relevant biomarkers, and objective recognition of the pain levels in PD patients remain less understood.
We recorded bilateral STN signals from PD patients implanted with adaptive deep brain stimulation (DBS) systems and collected pain rating series during in-hospital recovery. Patients provided pain annotations prior to surgery that inform the location (specific or non-specific) and PD-association with pain (PD-related or non-PD-related). A machine learning model was trained to classify higher versus lower pain states, from the eight pain annotation series of the six patients, using features derived from STN signals.
STN activity significantly classified the pain intensity in the PD-related pain group. Feature analysis indicated that STN activity from both sides can impact pain classification, with gamma and beta bands in the contralateral STN and delta and theta bands in the ipsilateral STN exhibiting a prominent role. Our observational study demonstrates a novel approach to decoding pain states and identifying STN biomarkers linked to PD-related pain.
{"title":"Wirelessly transmitted subthalamic nucleus signals decode endogenous pain levels in Parkinson's disease patients","authors":"Abdi Reza , Takufumi Yanagisawa , Naoki Tani , Ryohei Fukuma , Takuto Emura , Satoru Oshino , Ben Seymour , Haruhiko Kishima","doi":"10.1016/j.nbd.2025.107235","DOIUrl":"10.1016/j.nbd.2025.107235","url":null,"abstract":"<div><div>Pain is a prominent non-motor symptom of Parkinson's disease (PD); it may appear in various levels (elevated or diminished) during waking hours and substantially reduces quality of life. Although subthalamic nucleus (STN) signal analysis has dramatically advanced our comprehension of PD, the roles of bilateral STN, the relevant biomarkers, and objective recognition of the pain levels in PD patients remain less understood.</div><div>We recorded bilateral STN signals from PD patients implanted with adaptive deep brain stimulation (DBS) systems and collected pain rating series during in-hospital recovery. Patients provided pain annotations prior to surgery that inform the location (specific or non-specific) and PD-association with pain (PD-related or non-PD-related). A machine learning model was trained to classify higher versus lower pain states, from the eight pain annotation series of the six patients, using features derived from STN signals.</div><div>STN activity significantly classified the pain intensity in the PD-related pain group. Feature analysis indicated that STN activity from both sides can impact pain classification, with gamma and beta bands in the contralateral STN and delta and theta bands in the ipsilateral STN exhibiting a prominent role. Our observational study demonstrates a novel approach to decoding pain states and identifying STN biomarkers linked to PD-related pain.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107235"},"PeriodicalIF":5.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828149","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}
Pub Date : 2025-12-16DOI: 10.1016/j.nbd.2025.107227
Poorna Manasa Bhamidimarri , Khalood Alhosani , Heng Cai , Haya Al-Ali , Yara Marwan Abukhaled , Hasan Tawamie , Sahar Abdelaziz , Mouna Fawaz , Junaid Kashir , Yasmin Sajjad , Lamiya Mohiyiddeen , Michael Fakih , Hamdan Hamdan
The hippocampus, central to learning, memory, and social behavior, is increasingly implicated in the pathophysiology of autism spectrum disorder (ASD). Structural and functional disruptions in this region contribute to core ASD traits through impaired neurogenesis, abnormal dendritic morphology, excitatory/inhibitory imbalance, and altered connectivity with large-scale brain networks. Neuroimaging studies revealed changes in hippocampal volume, subfield-specific anomalies in the CA1 and dentate gyrus, and reduced functional connectivity within these regions. Genetic mutations in Shank3, Syngap1, Fmr1, and Nlgn3 disrupt synaptic plasticity and social memory circuits, while epigenetic alterations and environmental exposures further impair regulatory processes. Neuroinflammation exacerbates ASD pathology through microglial activation and cytokine release. Collectively, current evidence positions hippocampal dysfunction as central to ASD, emphasizing its relevance as both a biomarker and a therapeutic target to improve clinical outcomes.
{"title":"Review on the role of hippocampus in autism spectrum disorder: Recent insights into neuropathology, genetics, and emerging therapeutic strategies","authors":"Poorna Manasa Bhamidimarri , Khalood Alhosani , Heng Cai , Haya Al-Ali , Yara Marwan Abukhaled , Hasan Tawamie , Sahar Abdelaziz , Mouna Fawaz , Junaid Kashir , Yasmin Sajjad , Lamiya Mohiyiddeen , Michael Fakih , Hamdan Hamdan","doi":"10.1016/j.nbd.2025.107227","DOIUrl":"10.1016/j.nbd.2025.107227","url":null,"abstract":"<div><div>The hippocampus, central to learning, memory, and social behavior, is increasingly implicated in the pathophysiology of autism spectrum disorder (ASD). Structural and functional disruptions in this region contribute to core ASD traits through impaired neurogenesis, abnormal dendritic morphology, excitatory/inhibitory imbalance, and altered connectivity with large-scale brain networks. Neuroimaging studies revealed changes in hippocampal volume, subfield-specific anomalies in the CA1 and dentate gyrus, and reduced functional connectivity within these regions. Genetic mutations in <em>Shank3</em>, <em>Syngap1</em>, <em>Fmr1</em>, and <em>Nlgn3</em> disrupt synaptic plasticity and social memory circuits, while epigenetic alterations and environmental exposures further impair regulatory processes. Neuroinflammation exacerbates ASD pathology through microglial activation and cytokine release. Collectively, current evidence positions hippocampal dysfunction as central to ASD, emphasizing its relevance as both a biomarker and a therapeutic target to improve clinical outcomes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107227"},"PeriodicalIF":5.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781533","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}
Pub Date : 2025-12-13DOI: 10.1016/j.nbd.2025.107226
Brynna T. Webb , Hieu Trinh , Emily A. Breach , Kendall M. Foote , Erica Binelli , Geoffrey T. Swanson
De novo variants in a subset of ionotropic glutamate receptor (iGluR) genes cause nonsyndromic neurodevelopmental disorders (NDDs). Two recurrent variants in the kainate receptor (KAR) gene GRIK2 result in the gain-of-function (GoF) substitutions p.Ala657Thr and p.Thr660Lys in a critical pore-forming domain of the GluK2 subunit. Disorders in individuals with these variants manifest as intellectual disability, developmental delay, motor impairments, and, in the case of p.Thr660Lys, epilepsy. To explore their pathogenicity and phenotypic consequences in vivo, we generated knock-in mouse models harboring orthologous Grik2 mutations. Behavioral analyses revealed a range of developmental, motor, cognitive, and naturalistic behavior impairments in both lines, with the mouse model of the variant p.Thr660Lys, GluK2(T660K), exhibiting more severe phenotypes, consistent with clinical observations in humans. GluK2(T660K) mice also display interictal EEG abnormalities and handling-induced seizures. These models establish the first in vivo platforms for dissecting the underlying mechanisms of NDDs caused by GoF mutations in the GluK2 KAR subunit and represent crucial tools for therapeutic development.
{"title":"Pathological gain-of-function human variants in the GRIK2 kainate receptor gene cause wide-ranging behavioral dysfunction and seizures in mouse models","authors":"Brynna T. Webb , Hieu Trinh , Emily A. Breach , Kendall M. Foote , Erica Binelli , Geoffrey T. Swanson","doi":"10.1016/j.nbd.2025.107226","DOIUrl":"10.1016/j.nbd.2025.107226","url":null,"abstract":"<div><div><em>De novo</em> variants in a subset of ionotropic glutamate receptor (iGluR) genes cause nonsyndromic neurodevelopmental disorders (NDDs). Two recurrent variants in the kainate receptor (KAR) gene <em>GRIK2</em> result in the gain-of-function (GoF) substitutions p.Ala657Thr and p.Thr660Lys in a critical pore-forming domain of the GluK2 subunit. Disorders in individuals with these variants manifest as intellectual disability, developmental delay, motor impairments, and, in the case of p.Thr660Lys, epilepsy. To explore their pathogenicity and phenotypic consequences <em>in vivo</em>, we generated knock-in mouse models harboring orthologous <em>Grik2</em> mutations. Behavioral analyses revealed a range of developmental, motor, cognitive, and naturalistic behavior impairments in both lines, with the mouse model of the variant p.Thr660Lys, GluK2(T660K), exhibiting more severe phenotypes, consistent with clinical observations in humans. GluK2(T660K) mice also display interictal EEG abnormalities and handling-induced seizures. These models establish the first <em>in vivo</em> platforms for dissecting the underlying mechanisms of NDDs caused by GoF mutations in the GluK2 KAR subunit and represent crucial tools for therapeutic development.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107226"},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757153","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}
Pub Date : 2025-12-13DOI: 10.1016/j.nbd.2025.107224
Haoran Wang , Yuanzheng Qiao , Haimin Lu , Xitong Bo , Fuxiang Chen , Niu Pu , Yilong Zhou , Qiong Cheng
The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.
{"title":"Central integration mechanisms of neurovascular unit dysfunction and novel synergistic therapeutic strategies","authors":"Haoran Wang , Yuanzheng Qiao , Haimin Lu , Xitong Bo , Fuxiang Chen , Niu Pu , Yilong Zhou , Qiong Cheng","doi":"10.1016/j.nbd.2025.107224","DOIUrl":"10.1016/j.nbd.2025.107224","url":null,"abstract":"<div><div>The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107224"},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757164","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}
Pub Date : 2025-12-12DOI: 10.1016/j.nbd.2025.107223
Neil Donison , Matthew A. Hintermayer , Jacqueline Palik , Jessica Fisher , Kathryn Volkening , Michael J. Strong
The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau in vitro, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.
{"title":"MAPK family members differentially regulate pThr175 tau-mediated pathogenicity","authors":"Neil Donison , Matthew A. Hintermayer , Jacqueline Palik , Jessica Fisher , Kathryn Volkening , Michael J. Strong","doi":"10.1016/j.nbd.2025.107223","DOIUrl":"10.1016/j.nbd.2025.107223","url":null,"abstract":"<div><div>The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau <em>in vitro</em>, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107223"},"PeriodicalIF":5.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757099","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}
Pub Date : 2025-12-12DOI: 10.1016/j.nbd.2025.107222
Kelsey Bernard , Mandi J. Corenblum , Paola Tonino , Lalitha Madhavan
Patient induced pluripotent stem cell (iPSC)-based models represent a powerful human system to gain insights into the etiopathology of Parkinson's disease (PD). Here, we studied several iPSC-derived dopamine neuron (iPSC-DAN) lines, from individuals with idiopathic PD, which is the most common form of PD. Specifically, using iPSC-DAN differentiated for 50–55 days, we performed an in-depth analysis of different bioenergetic pathways and cellular quality control mechanisms in the cells. Our results showed wide ranging impairments in oxidative phosphorylation (OXPHOS), glycolysis and creatine kinase pathways in the PD dopamine (DA) neurons. Specifically, the PD neurons exhibited reduced oxygen consumption rates (OCR) at baseline and after challenges with mitochondrial inhibitors, as well as decreased glycolytic reserves measured via ECAR. This translated to lower OCR:ECAR ratios signifying more reliance on glycolysis vs OXPHOS in the PD cells. Moreover, a mislocalization of creatine kinase B to mitochondria was seen in the PD cells. These energetic changes occurred alongside the enhanced expression of mitochondrial fission proteins, disrupted mitophagy and oxidative stress. Additionally, the PD neurons contained more monomeric, phosphorylated, and aggregated forms of alpha synuclein and displayed reduced viability. Ultrastructural examination through immuno-electron microscopy showed more alpha synuclein gold particles directly associated with mitochondria and packed into autophagic vesicles. In essence, these data capture a web of key changes, associated with neuronal degeneration, in human iPSC-DAN from persons with idiopathic PD.
{"title":"Bioenergetic and protein processing imbalances in iPSC-dopamine neurons from individuals with idiopathic Parkinson's disease","authors":"Kelsey Bernard , Mandi J. Corenblum , Paola Tonino , Lalitha Madhavan","doi":"10.1016/j.nbd.2025.107222","DOIUrl":"10.1016/j.nbd.2025.107222","url":null,"abstract":"<div><div>Patient induced pluripotent stem cell (iPSC)-based models represent a powerful human system to gain insights into the etiopathology of Parkinson's disease (PD). Here, we studied several iPSC-derived dopamine neuron (iPSC-DAN) lines, from individuals with idiopathic PD, which is the most common form of PD. Specifically, using iPSC-DAN differentiated for 50–55 days, we performed an in-depth analysis of different bioenergetic pathways and cellular quality control mechanisms in the cells. Our results showed wide ranging impairments in oxidative phosphorylation (OXPHOS), glycolysis and creatine kinase pathways in the PD dopamine (DA) neurons. Specifically, the PD neurons exhibited reduced oxygen consumption rates (OCR) at baseline and after challenges with mitochondrial inhibitors, as well as decreased glycolytic reserves measured via ECAR. This translated to lower OCR:ECAR ratios signifying more reliance on glycolysis vs OXPHOS in the PD cells. Moreover, a mislocalization of creatine kinase B to mitochondria was seen in the PD cells. These energetic changes occurred alongside the enhanced expression of mitochondrial fission proteins, disrupted mitophagy and oxidative stress. Additionally, the PD neurons contained more monomeric, phosphorylated, and aggregated forms of alpha synuclein and displayed reduced viability. Ultrastructural examination through immuno-electron microscopy showed more alpha synuclein gold particles directly associated with mitochondria and packed into autophagic vesicles. In essence, these data capture a web of key changes, associated with neuronal degeneration, in human iPSC-DAN from persons with idiopathic PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107222"},"PeriodicalIF":5.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757079","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}
Pub Date : 2025-12-08DOI: 10.1016/j.nbd.2025.107218
Angela Lanciotti , Maria Stefania Brignone , Chiara De Nuccio , Sara Sposito , Elena Sofia Caprini , Marcello Belfiore , Francesco Nicita , Caterina Veroni , Chiara Meloni , Rosalba Carrozzo , Teresa Rizza , Chiara Aiello , Jacopo Sartorelli , Enrico Bertini , Sergio Visentin , Elena Ambrosini
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by astrocyte dysfunction. Mutations in the MLC1 gene, which encodes the astrocyte-specific membrane protein MLC1 represent the main cause. MLC is characterized by myelin vacuolation, subcortical cysts, and brain edema. Clinically, patients show motor impairments such as ataxia and spasticity, and epilepsy. Currently, the function of MLC1 and the molecular mechanisms underlying MLC remain poorly understood, limiting therapeutic development. This is especially relevant since symptom reversibility has been observed in some patients.
To date, functional studies have mainly relied on mouse models, which do not fully reproduce human pathology. To develop a more relevant disease model, we generated astrocytes from induced pluripotent stem cells (iPSCs) derived from fibroblasts of three healthy donors and three MLC patients.
Using molecular, biochemical, electrophysiological, and imaging approaches, we found that MLC astrocytes show impaired volume regulation, cytoplasmic vacuolation, and altered EGF receptor expression, consistent with prior MLC models. Notably, we also revealed endosomal alterations, increased proliferation, and abnormal expression of the critical astrocyte maturation markers EAAT1, GFAP, Cx43, AQP4, and Kir4.1, the latter causing impaired potassium currents in patient-derived cells.
These results provide the first evidence that MLC1 mutations alter astrocyte maturation and potassium homeostasis, potentially contributing to disease pathogenesis.
Our patient-specific iPSC-derived model offers novel insights into the molecular basis of MLC and highlights the role of MLC1 in astrocyte development. This platform represents a valuable tool for preclinical drug screening and supports the development of personalized therapeutic strategies for this rare leukodystrophy.
{"title":"Astrocytes differentiated from patient iPSCs model the rare leukodystrophy MLC and uncover disease-linked maturation defects and Kir4.1 channel dysfunction","authors":"Angela Lanciotti , Maria Stefania Brignone , Chiara De Nuccio , Sara Sposito , Elena Sofia Caprini , Marcello Belfiore , Francesco Nicita , Caterina Veroni , Chiara Meloni , Rosalba Carrozzo , Teresa Rizza , Chiara Aiello , Jacopo Sartorelli , Enrico Bertini , Sergio Visentin , Elena Ambrosini","doi":"10.1016/j.nbd.2025.107218","DOIUrl":"10.1016/j.nbd.2025.107218","url":null,"abstract":"<div><div>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by astrocyte dysfunction. Mutations in the <em>MLC1</em> gene, which encodes the astrocyte-specific membrane protein MLC1 represent the main cause. MLC is characterized by myelin vacuolation, subcortical cysts, and brain edema. Clinically, patients show motor impairments such as ataxia and spasticity, and epilepsy. Currently, the function of MLC1 and the molecular mechanisms underlying MLC remain poorly understood, limiting therapeutic development. This is especially relevant since symptom reversibility has been observed in some patients.</div><div>To date, functional studies have mainly relied on mouse models, which do not fully reproduce human pathology. To develop a more relevant disease model, we generated astrocytes from induced pluripotent stem cells (iPSCs) derived from fibroblasts of three healthy donors and three MLC patients.</div><div>Using molecular, biochemical, electrophysiological, and imaging approaches, we found that MLC astrocytes show impaired volume regulation, cytoplasmic vacuolation, and altered EGF receptor expression, consistent with prior MLC models. Notably, we also revealed endosomal alterations, increased proliferation, and abnormal expression of the critical astrocyte maturation markers EAAT1, GFAP, Cx43, AQP4, and Kir4.1, the latter causing impaired potassium currents in patient-derived cells.</div><div>These results provide the first evidence that MLC1 mutations alter astrocyte maturation and potassium homeostasis, potentially contributing to disease pathogenesis.</div><div>Our patient-specific iPSC-derived model offers novel insights into the molecular basis of MLC and highlights the role of MLC1 in astrocyte development. This platform represents a valuable tool for preclinical drug screening and supports the development of personalized therapeutic strategies for this rare leukodystrophy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107218"},"PeriodicalIF":5.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724897","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}
Pub Date : 2025-12-08DOI: 10.1016/j.nbd.2025.107220
Pengcheng Liang , Tao Chen , Yena Che , Nan Zhang , Xinyue Zhang , Na Wang , Yuanyuan Wang , Yiwen Chen , Zhenyu Cheng , Changhu Liang , Lingfei Guo , Meng Li
Background
Cerebral small vessel disease (CSVD) causes cortical atrophy and motor decline, but the specific cortical regions involved and their mediating role remain unclear. We aimed to determine whether regional cortical thickness mediates the association between CSVD severity and motor function.
Methods and materials
We recruited 354 participants with CSVD (mean age 57.2 ± 11.4 years), of whom 55 had 16-month follow-up. Participants underwent 3.0 T MRI with 3D T1-weighted MPRAGE (1 mm3 isotropic) and motor testing (TUG and 3-m walk test). Cortical thickness was quantified using FreeSurfer v6.0 with longitudinal processing for follow-up scans. General linear models tested cross-sectional associations, linear mixed-effects models examined longitudinal effects, and mediation analysis assessed indirect effects.
Results
Significant negative associations were observed between cortical thickness and CSVD severity in the right insula, left rostral anterior cingulate cortex, and left lateral occipital cortex. Additionally, significant associations were found between cortical thickness at multiple time points in the right insula (β = 0.594, P = 0.024) and TUG test scores. The thickness of the right insular cortex mediated the relationship between CSVD severity and TUG performance (mean [SE] indirect effect, 0.085 [0.045]; 95 % CI, 0.015–0.197).
Conclusions
CSVD severity was associated with cortical thinning in specific cortical regions, and right insular cortical thickness levels were related to motor performance and partially mediated the association between CSVD severity and mobility impairment.
Ethics approval and consent to participate
All study procedures were approved by the Ethical Committee of the Institutional Review Board (IRB) of the Shandong Institute of Medical Imaging (2019–002). The study was conducted in accordance with the Declaration of Helsinki. All participants signed an informed consent form before the commencement of the study.
{"title":"Cortical and subcortical gray matter alterations link cerebral small vessel disease burden to motor slowing: A cross-sectional and longitudinal study","authors":"Pengcheng Liang , Tao Chen , Yena Che , Nan Zhang , Xinyue Zhang , Na Wang , Yuanyuan Wang , Yiwen Chen , Zhenyu Cheng , Changhu Liang , Lingfei Guo , Meng Li","doi":"10.1016/j.nbd.2025.107220","DOIUrl":"10.1016/j.nbd.2025.107220","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral small vessel disease (CSVD) causes cortical atrophy and motor decline, but the specific cortical regions involved and their mediating role remain unclear. We aimed to determine whether regional cortical thickness mediates the association between CSVD severity and motor function.</div></div><div><h3>Methods and materials</h3><div><em>We</em> recruited 354 participants with CSVD (mean age 57.2 ± 11.4 years), of whom 55 had 16-month follow-up. Participants underwent 3.0 T MRI with 3D T1-weighted MPRAGE (1 mm<sup>3</sup> isotropic) and motor testing (TUG and 3-m walk test). Cortical thickness was quantified using FreeSurfer v6.0 with longitudinal processing for follow-up scans. General linear models tested cross-sectional associations, linear mixed-effects models examined longitudinal effects, and mediation analysis assessed indirect effects.</div></div><div><h3>Results</h3><div>Significant negative associations were observed between cortical thickness and CSVD severity in the right insula, left rostral anterior cingulate cortex, and left lateral occipital cortex. Additionally, significant associations were found between cortical thickness at multiple time points in the right insula (β = 0.594, <em>P</em> = 0.024) and TUG test scores. The thickness of the right insular cortex mediated the relationship between CSVD severity and TUG performance (mean [SE] indirect effect, 0.085 [0.045]; 95 % CI, 0.015–0.197).</div></div><div><h3>Conclusions</h3><div>CSVD severity was associated with cortical thinning in specific cortical regions, and right insular cortical thickness levels were related to motor performance and partially mediated the association between CSVD severity and mobility impairment.</div></div><div><h3>Ethics approval and consent to participate</h3><div>All study procedures were approved by the Ethical Committee of the Institutional Review Board (IRB) of the Shandong Institute of Medical Imaging (2019–002). The study was conducted in accordance with the Declaration of Helsinki. All participants signed an informed consent form before the commencement of the study.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107220"},"PeriodicalIF":5.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724924","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}
Pub Date : 2025-12-08DOI: 10.1016/j.nbd.2025.107221
Zhong-Yun Chen , Jia-Hui Hou , Min Chu , Yi-Hao Wang , Rui Liu , Jing Zhang , Hong Ye , Miao Qu , Li-Yong Wu
Introduction
Systemic metabolic and inflammatory disturbances are implicated in neurodegenerative diseases, but comprehensive metabolomic profiling in Creutzfeldt–Jakob disease (CJD) remains limited, and the potential interplay between peripheral metabolism and inflammatory or tissue-remodeling processes is poorly understood.
Objectives
This study aimed to characterize the plasma metabolome and inflammatory/proteolytic profile in CJD, and to evaluate their individual and combined associations with cerebral glucose metabolism and clinical severity.
Methods
From January 2020 to July 2023, we recruited patients with probable or definite genetic CJD and age- and sex-matched healthy controls (HCs) at Xuanwu Hospital. All participants underwent plasma metabolomic profiling, cytokine testing, brain 18F-FDG PET/MRI, and clinical assessments. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) identified differentially abundant metabolites (variable importance in projection >1, p < 0.05). Linear and interaction models, adjusted for age and sex, evaluated associations with cerebral hypometabolism and clinical outcomes.
Results
We enrolled 40 CJD patients (mean age 60.8 years, 42.5 % female) and 40 HCs. OPLS-DA revealed clear separation between groups, and 42 differentially abundant metabolites were identified from the initial 163 metabolites that differed between groups. Enrichment analysis revealed dysregulation in metabolic pathways related to amino acid biosynthesis, alanine, aspartate and glutamate metabolism, ABC transporters, glycerophospholipid metabolism, and others. Levels of IL-4, IL-18, IL-22, IFN-γ, IL-1β, IL-6, MMP-1, and MMP-8 were significantly elevated in CJD patients. Multiple metabolites and these peripheral factors correlated with hypometabolism in vulnerable brain regions and with cognitive and functional decline. Interaction analyses further showed that specific metabolite–mediator combinations (e.g., Glycerophosphocholine, Glyceric acid, Asparagine, Dimethylglycine, 3-Phosphoglycerate with IL-1β, IL-4, IL-6, IL-22, MMP-8) were significantly associated with regional hypometabolism and clinical deterioration.
Conclusion
CJD involves coupled peripheral metabolic and inflammatory/proteolytic disturbances that may be associated with more severe brain degeneration and clinical decline, suggesting a possible multifaceted systemic component accompanying disease pathology.
系统性代谢和炎症紊乱与神经退行性疾病有关，但克雅氏病（CJD）的全面代谢组学分析仍然有限，外周代谢与炎症或组织重塑过程之间的潜在相互作用尚不清楚。目的：本研究旨在表征克雅氏病的血浆代谢组和炎症/蛋白水解谱，并评估它们与脑糖代谢和临床严重程度的个体和联合关联。方法：从2020年1月至2023年7月，我们在宣武医院招募了可能或确定的遗传性CJD患者和年龄和性别匹配的健康对照（hc）。所有参与者都进行了血浆代谢组学分析、细胞因子测试、脑18F-FDG PET/MRI和临床评估。正交预测到潜在结构-判别分析（OPLS-DA）鉴定出差异丰富的代谢物（预测的可变重要性bbb1， p ）结果：我们招募了40名CJD患者（平均年龄60.8 岁，女性42.5 %）和40名hc患者。OPLS-DA显示各组之间存在明显的分离，从163个初始代谢物中鉴定出42个差异丰富的代谢物。富集分析显示与氨基酸生物合成、丙氨酸、天冬氨酸和谷氨酸代谢、ABC转运蛋白、甘油磷脂代谢等相关的代谢途径失调。CJD患者IL-4、IL-18、IL-22、IFN-γ、IL-1β、IL-6、MMP-1、MMP-8水平显著升高。多种代谢物和这些外围因素与大脑脆弱区域的代谢低下以及认知和功能下降相关。相互作用分析进一步表明，特定代谢物-介质组合（如甘油酰胆碱、甘油三酸、天冬酰胺、二甲基甘氨酸、3-磷酸甘油酸与IL-1β、IL-4、IL-6、IL-22、MMP-8）与局部低代谢和临床恶化显著相关。结论：克雅氏病涉及外周代谢和炎症/蛋白水解紊乱，这些紊乱可能与更严重的脑变性和临床衰退有关，提示可能存在伴随疾病病理的多方面系统性成分。
{"title":"Integrated peripheral metabolic and inflammatory biomarker signatures are associated with clinical deterioration in Creutzfeldt–Jakob disease","authors":"Zhong-Yun Chen , Jia-Hui Hou , Min Chu , Yi-Hao Wang , Rui Liu , Jing Zhang , Hong Ye , Miao Qu , Li-Yong Wu","doi":"10.1016/j.nbd.2025.107221","DOIUrl":"10.1016/j.nbd.2025.107221","url":null,"abstract":"<div><h3>Introduction</h3><div>Systemic metabolic and inflammatory disturbances are implicated in neurodegenerative diseases, but comprehensive metabolomic profiling in Creutzfeldt–Jakob disease (CJD) remains limited, and the potential interplay between peripheral metabolism and inflammatory or tissue-remodeling processes is poorly understood.</div></div><div><h3>Objectives</h3><div>This study aimed to characterize the plasma metabolome and inflammatory/proteolytic profile in CJD, and to evaluate their individual and combined associations with cerebral glucose metabolism and clinical severity.</div></div><div><h3>Methods</h3><div>From January 2020 to July 2023, we recruited patients with probable or definite genetic CJD and age- and sex-matched healthy controls (HCs) at Xuanwu Hospital. All participants underwent plasma metabolomic profiling, cytokine testing, brain <sup>18</sup>F-FDG PET/MRI, and clinical assessments. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) identified differentially abundant metabolites (variable importance in projection >1, <em>p</em> < 0.05). Linear and interaction models, adjusted for age and sex, evaluated associations with cerebral hypometabolism and clinical outcomes.</div></div><div><h3>Results</h3><div>We enrolled 40 CJD patients (mean age 60.8 years, 42.5 % female) and 40 HCs. OPLS-DA revealed clear separation between groups, and 42 differentially abundant metabolites were identified from the initial 163 metabolites that differed between groups. Enrichment analysis revealed dysregulation in metabolic pathways related to amino acid biosynthesis, alanine, aspartate and glutamate metabolism, ABC transporters, glycerophospholipid metabolism, and others. Levels of IL-4, IL-18, IL-22, IFN-γ, IL-1β, IL-6, MMP-1, and MMP-8 were significantly elevated in CJD patients. Multiple metabolites and these peripheral factors correlated with hypometabolism in vulnerable brain regions and with cognitive and functional decline. Interaction analyses further showed that specific metabolite–mediator combinations (e.g., Glycerophosphocholine, Glyceric acid, Asparagine, Dimethylglycine, 3-Phosphoglycerate with IL-1β, IL-4, IL-6, IL-22, MMP-8) were significantly associated with regional hypometabolism and clinical deterioration.</div></div><div><h3>Conclusion</h3><div>CJD involves coupled peripheral metabolic and inflammatory/proteolytic disturbances that may be associated with more severe brain degeneration and clinical decline, suggesting a possible multifaceted systemic component accompanying disease pathology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107221"},"PeriodicalIF":5.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724950","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}
Pub Date : 2025-12-06DOI: 10.1016/j.nbd.2025.107219
Tae-Yong Choi , Aileen Gunawan , DaYeong Seo , Jinkyu Park , Eun Hee Ahn , Sang Won Suh , Marc V. Fuccillo , Kyuhyun Choi
Autism spectrum disorder (ASD) is heterogeneous at every level, from behavior to molecular pathways, limiting the value of subgrouping schemes built on surface phenotypes alone. We synthesize evidence that biologically anchored subtypes, defined by convergent genetics, developmental timing, and brain–body crosstalk, offer a tractable path to precision medicine. Leveraging advances in large-scale genomic resources and computational analytics, we propose a multi-axis framework: (i) genetic architecture spanning rare variants and polygenic load, (ii) developmental windows from mid-gestation to infancy divergence and regression, and (iii) brain–body interactions shaping plasticity and symptom expression. This framework enables mechanism-guided therapeutic strategies through biomarker-stratified enrollment, target-engagement readouts, and circuit-anchored outcomes. Preclinical platforms, genetically engineered mice and patient-derived induced pluripotent stem cells (iPSCs), demonstrate convergence onto limited synaptic and connectivity “neurotypes,” enabling causal links from gene to circuit to behavior and proof-of-concept rescue. We close with priorities: standardized multi-platform characterization, decision tools linking subtype labels to interventions, and stratified trials that co-report clinical and biological endpoints, with ethical guardrails to ensure early stratification expands opportunity while advancing individualized care.
{"title":"Applying biologically anchored subtypes to advance precision medicine in autism spectrum disorder","authors":"Tae-Yong Choi , Aileen Gunawan , DaYeong Seo , Jinkyu Park , Eun Hee Ahn , Sang Won Suh , Marc V. Fuccillo , Kyuhyun Choi","doi":"10.1016/j.nbd.2025.107219","DOIUrl":"10.1016/j.nbd.2025.107219","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is heterogeneous at every level, from behavior to molecular pathways, limiting the value of subgrouping schemes built on surface phenotypes alone. We synthesize evidence that biologically anchored subtypes, defined by convergent genetics, developmental timing, and brain–body crosstalk, offer a tractable path to precision medicine. Leveraging advances in large-scale genomic resources and computational analytics, we propose a multi-axis framework: (i) genetic architecture spanning rare variants and polygenic load, (ii) developmental windows from mid-gestation to infancy divergence and regression, and (iii) brain–body interactions shaping plasticity and symptom expression. This framework enables mechanism-guided therapeutic strategies through biomarker-stratified enrollment, target-engagement readouts, and circuit-anchored outcomes. Preclinical platforms, genetically engineered mice and patient-derived induced pluripotent stem cells (iPSCs), demonstrate convergence onto limited synaptic and connectivity “neurotypes,” enabling causal links from gene to circuit to behavior and proof-of-concept rescue. We close with priorities: standardized multi-platform characterization, decision tools linking subtype labels to interventions, and stratified trials that co-report clinical and biological endpoints, with ethical guardrails to ensure early stratification expands opportunity while advancing individualized care.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107219"},"PeriodicalIF":5.6,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708625","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}
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