Journal of Neurochemistry最新文献

{"title":"Inhibition of cGMP-Signalling Rescues Retinal Ganglion Cells From Axotomy-Induced Degeneration","authors":"Katia Ihadadene,&nbsp;Azdah Hamed A Fallatah,&nbsp;Yu Zhu,&nbsp;Arianna Tolone,&nbsp;François Paquet-Durand","doi":"10.1111/jnc.70072","DOIUrl":"https://doi.org/10.1111/jnc.70072","url":null,"abstract":"<p>The axons of retinal ganglion cells (RGCs) form the optic nerve, which relays visual information to the brain. RGC degeneration is the root cause of a variety of blinding diseases linked to optic nerve damage, including glaucoma, the second leading cause of blindness worldwide. The underlying cellular mechanisms of RGC degeneration are largely unclear; yet, they have been connected to excessive production of the signalling molecule nitric oxide (NO) by nitric oxide synthase (NOS). NO activates soluble guanylate cyclase (sGC), which subsequently produces the second messenger cyclic guanosine monophosphate (cGMP). This, in turn, activates protein kinase G (PKG), which can phosphorylate downstream protein targets. To study the role of NO/cGMP/PKG signalling in RGC degeneration, we used organotypic retinal explant cultures in which the optic nerve had been severed. We assessed the activity of NOS, RGC death and survival at different times after optic nerve transection. While NOS activity was high right after optic nerve transection, significant RGC loss occurred with a 24–48-h delay. We then treated retinal explants with inhibitors selectively targeting either NOS, sGC, PKG, or Kv1.3 and Kv1.6 voltage-gated potassium channels. While all four treatments reduced RGC death, the PKG inhibitor CN238 and the Kv-channel blocker Margatoxin (MrgX) showed the most pronounced rescue effects. Our results confirm an involvement of NO/cGMP/PKG signalling in RGC degeneration, highlight the potential of PKG and Kv1-channel targeting drugs for treatment development, and further suggest organotypic retinal explant cultures as a useful model for investigations into optic nerve damage.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases","authors":"Ingrid Prata Mendonça,&nbsp;Christina Alves Peixoto","doi":"10.1111/jnc.70069","DOIUrl":"https://doi.org/10.1111/jnc.70069","url":null,"abstract":"<p>Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut–brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Propofol-Induced Cognitive Impairment: Suppression of Critical Hippocampal Pathways","authors":"Xueyue Zhou,&nbsp;Shasha Dong,&nbsp;Yuhai Xu","doi":"10.1111/jnc.70070","DOIUrl":"https://doi.org/10.1111/jnc.70070","url":null,"abstract":"<div>\u0000 \u0000 <p>Propofol, a commonly used anesthetic, is known to cause postoperative cognitive dysfunction (POCD), particularly after prolonged or high-dose administration. Its effects on neural remodeling in the hippocampal region, which is vital for cognitive function, remain poorly understood. This study employs single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptomic analysis to elucidate the molecular mechanisms by which propofol impairs hippocampal neural remodeling. Our findings indicate that propofol suppresses the (5-Hydroxytryptamine Receptor 1A/Glutamate Receptor 2/Phosphoinositide 3-Kinase Regulatory Subunit 1) HTR1A/GRIA2/PIK3R1 signaling pathway, contributing to cognitive dysfunction in mice. In vitro experiments reveal that propofol treatment reduces the expression of HTR1A/GRIA2/PIK3R1-related factors, decreases neuronal activity and synaptic plasticity, and increases apoptosis and inflammation. In vivo experiments demonstrate significant impairments in spatial memory and learning abilities in mice treated with propofol. These results provide new insights into the long-term effects of anesthetic drugs and offer a scientific basis for their judicious use in clinical practice. The study highlights potential strategies and targets for preventing and treating POCD, emphasizing the importance of understanding the molecular mechanisms underlying anesthetic-induced cognitive dysfunction.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861882","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":"Preface to the Special Issue “Touchscreen Testing to Investigate the Neurochemistry of Cognition”","authors":"Miguel Skirzewski,&nbsp;Lisa M. Saksida,&nbsp;Tim J. Bussey","doi":"10.1111/jnc.70071","DOIUrl":"https://doi.org/10.1111/jnc.70071","url":null,"abstract":"<p>Touchscreen-based methodologies have enabled significant advancements in cognitive neuroscience by providing standardized, translationally relevant assessments of advanced cognitive functions in rodent models. This special issue highlights the potential of these systems to bridge animal and human research, providing insights into the neurochemical and biological mechanisms underlying cognition. The included studies explore diverse applications, from understanding the cognitive impacts of chronic stress and maternal immune activation to evaluating the effectiveness of novel therapeutics and assessing cross-species cognitive testing approaches that enhance translational relevance. By combining touchscreen technologies with cutting-edge approaches like electrophysiology and open science databases, these contributions underscore the critical role of automated systems in advancing translational research. Together, they lay the foundation for novel therapeutic strategies to address cognitive deficits in brain disorders.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Diseases and Brain Disorders: Genetic Mechanisms and Biomarker Pathways in a Prospective Cohort Study From the UK Biobank","authors":"Hai-Hua Guo,&nbsp;Pei-Yang Gao,&nbsp;Wei Zhang,&nbsp;Yan Fu,&nbsp;Hao-Chen Chi,&nbsp;Zi-Hao Zhang,&nbsp;Shuang-Ling Han,&nbsp;Bao-Lin Han,&nbsp;Yu-Ying Zhang,&nbsp;Wei Xu,&nbsp;Lan Tan,&nbsp;Hui-Fu Wang","doi":"10.1111/jnc.70066","DOIUrl":"https://doi.org/10.1111/jnc.70066","url":null,"abstract":"<div>\u0000 \u0000 <p>Population-based evidence directly linking liver diseases to brain disorders is limited, and its genetic and biochemical associations remain unclear. Our aim is to examine the links between liver diseases and brain disorders. This prospective cohort study utilized data from 492 059 participants in the UK Biobank. We identified 508 cases of alcoholic liver disease (ALD), 583 cases of non-alcoholic fatty liver disease (NAFLD), and 557 cases of viral hepatitis (VH) based on International Classification of Diseases (ICD) codes. Initially, we employed multiple linear and logistic regression to assess associations between liver diseases, polygenic risk score (PRS), inflammatory and metabolic biomarkers, and brain function. Cox proportional hazard models were then applied to determine the impact of liver diseases on the incidence of brain disorders. Ultimately, structural equation models were used to explore potential genetic and biomarker pathways. During a median follow-up of 14.46 years, participants with ALD, NAFLD, and VH demonstrated poorer cognition, mental health, and motor function compared to the healthy group, with <i>p</i> &lt; 0.05 for false discovery rate (FDR-Q &lt; 0.05). They exhibited increased risks for dementia (hazard ratios [HRs]: 2.28–4.10; FDR-Q &lt; 0.001), major depressive disorder (HRs: 2.25–3.23; FDR-Q &lt; 0.001), and generalized anxiety disorder (HRs: 1.70–2.66; FDR-Q &lt; 0.01). Additionally, C-reactive protein, neutrophil-to-lymphocyte ratio, platelets, and low-density lipoprotein lipid components mediated the associations between PRS, liver diseases, and brain disorders. Our findings demonstrated that liver diseases were risk factors for brain disorders, with genetic and biochemical associations contributing to these risks.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831367","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":"Donepezil Improves PSD95 Expression, Mitigates Neuroinflammation via PI3K/Akt/NF-κB and Mitochondrial Dysfunction in a Rodent Model of Subarachnoid Haemorrhage","authors":"Ahmed Shaney Rehman,&nbsp;Ammar Tasleem,&nbsp;Nemat Ali,&nbsp;Rehan Khan,&nbsp;Mohd. Salman,&nbsp;Pravir Kumar,&nbsp;Suhel Parvez","doi":"10.1111/jnc.70063","DOIUrl":"https://doi.org/10.1111/jnc.70063","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondrial dysfunction is a known contributor to subarachnoid haemorrhage (SAH) induced early brain damage (EBI), leading to poor neurological outcomes. An experimental SAH model was induced in adult male Wistar rats using endovascular perforation. Donepezil, an acetylcholinesterase (AChE) inhibitor (1 or 2 mg/kg body weight), was administered intraperitoneally 4 h after SAH. The severity of cerebral cortex injury was assessed using blood clot grading, behavioral tests and H and E staining. We carried out an assessment of neuroinflammatory markers using western blotting and immunofluorescence. Additionally, we examined neuronal architecture using H and E staining, measured mitochondrial redox imbalance or ROS and membrane potential (Δѱm) and analyzed mitochondrial morphology using transmission electron microscopy (TEM). Apoptotic markers and mitochondrial respiratory complexes were assessed by western blotting. Our results indicated that donepezil treatment significantly upregulated PSD95, α7-AChR, CaMKII, BDNF, CREB, and PI3K expression in cerebral cortical neurons in response to SAH. This was accompanied by improved neurological function, reduced brain edema, decreased neuronal degeneration, and increased levels of OXPHOS and ATP. In the cerebral cortex, donepezil inhibited mitochondria-associated neuronal apoptosis after SAH as revealed by increased membrane potential integrity of mitochondria, reducing the ratio of Bax to Bcl-2 and inhibiting caspase-3 activity. Additionally, donepezil upregulated synaptic proteins (PSD95), strengthening synaptic connections and supporting spatial working memory circuits via the neurotrophic factor BDNF in post-SAH rats. Our research concludes that donepezil has neuroprotective benefits by inhibiting SAH-induced mitochondrial-mediated cell death through the regulation of Drp1-mediated mitochondrial morphology changes.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831366","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":"RETRACTION: Lithium Inhibits Aluminum-Induced Apoptosis in Rabbit Hippocampus, by Preventing Cytochrome c Translocation, Bcl-2 Decrease, Bax Elevation and Caspase-3 Activation","authors":"","doi":"10.1111/jnc.70065","DOIUrl":"https://doi.org/10.1111/jnc.70065","url":null,"abstract":"<p><b>RETRACTION</b>: O. Ghribi, M. M. Herman, N. K. Spaulding, and J. Savory, “Lithium Inhibits Aluminum-Induced Apoptosis in Rabbit Hippocampus, by Preventing Cytochrome c Translocation, Bcl-2 Decrease, Bax Elevation and Caspase-3 Activation,” <i>Journal of Neurochemistry</i> 82, no. 1 (2002): 137-145, https://doi.org/10.1046/j.1471-4159.2002.00957.x.</p><p>The above article, published online on 25 June 2002 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley &amp; Sons Ltd. A third party notified the journal about concerns of image duplication in this article. Further investigation by the publisher and the journal confirmed that images in Figure 2b had been duplicated and rotated, bands in Figure 3 had been duplicated and rotated, an image had been duplicated between Figure 4b(i) and Figure 5a, an actin band had been duplicated between Figure 2a and Figure 3, and band in Figure 1 had been potentially duplicated and resized. Some authors could not be reached, and the remaining authors otherwise did not respond to inquiries by the journal and publisher. The retraction has been agreed to because the evidence of image duplication, rotation, and resizing fundamentally compromises the conclusions presented in the article and, due to the lack of original data, the conclusions cannot be verified. The authors did not respond to our notice regarding the retraction.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators","authors":"Justin Lines,&nbsp;Michelle Corkrum,&nbsp;Juan Aguilar,&nbsp;Alfonso Araque","doi":"10.1111/jnc.70054","DOIUrl":"https://doi.org/10.1111/jnc.70054","url":null,"abstract":"<p>Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte–neuron interaction at tripartite synapses scales up to astrocyte–neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α2δ-1-Linked NMDA and AMPA Receptors in Neuropathic Pain and Gabapentinoid Action","authors":"Yuying Huang,&nbsp;Shao-Rui Chen,&nbsp;Hui-Lin Pan","doi":"10.1111/jnc.70064","DOIUrl":"https://doi.org/10.1111/jnc.70064","url":null,"abstract":"<p>Chronic neuropathic pain is a debilitating condition that presents a significant therapeutic challenge. Unlike nociceptive pain, neuropathic pain is predominantly driven by glutamate NMDA receptors (NMDARs) and/or Ca²⁺-permeable AMPA receptors (CP-AMPARs) at synapses between primary afferent nerves and excitatory neurons in the spinal dorsal horn. The α2δ-1 protein, encoded by <i>Cacna2d1</i> and historically recognized as a subunit of voltage-activated Ca²⁺ channels, is the primary target of gabapentinoids, such as gabapentin and pregabalin, which are widely prescribed for neuropathic pain and epilepsy. However, gabapentinoids have minimal effects on Ca²⁺ channel activity. Recent studies reveal that α2δ-1 plays a pivotal role in amplifying nociceptive input to the spinal cord in neuropathic pain. This action is mediated through its dynamic physical interactions with phosphorylated NMDARs and GluA1/GluA2 subunits via its intrinsically disordered C-terminal region. α2δ-1 not only promotes synaptic trafficking of NMDARs but also disrupts heteromeric assembly of GluA1/GluA2 subunits in the spinal dorsal horn. The central function of α2δ-1 is to elevate intracellular Ca²⁺ concentrations at both presynaptic and postsynaptic sites, augmenting nociceptive transmission. Consequently, α2δ-1 serves as a dual regulator coordinating synaptic expression of NMDARs and GluA1 homomeric CP-AMPARs, a function that underlies the therapeutic actions of gabapentinoids. By inhibiting α2δ-1, gabapentinoids reduce the hyperactivity of synaptic α2δ-1-bound NMDARs and CP-AMPARs, thereby dampening the excessive excitatory synaptic transmission characteristic of neuropathic pain. These newly identified roles of α2δ-1 in orchestrating glutamatergic synaptic plasticity suggest that gabapentinoids could be repurposed for treating other neurological disorders involving dysregulated synaptic NMDARs and CP-AMPARs.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs","authors":"Thasneem Musthafa,&nbsp;Syed Kavish Nizami,&nbsp;Ankita Mishra,&nbsp;Gaiti Hasan,&nbsp;Renjitha Gopurappilly","doi":"10.1111/jnc.70059","DOIUrl":"https://doi.org/10.1111/jnc.70059","url":null,"abstract":"<p>Parkinson's disease (PD) has emerged as a multisystem disorder affecting multiple cellular and organellar systems in addition to the dopaminergic neurons. Disease-specific induced pluripotent stem cells (iPSCs) model early developmental changes and cellular perturbations that are otherwise inaccessible from clinical settings. Here, we report the early changes in patient-derived iPSCs carrying a homozygous recessive mutation, R741Q, in the <i>PLA2G6</i> gene. A gene-edited R747W iPSC line mirrored these phenotypes, thus validating our initial findings. Bioenergetic dysfunction and hyperpolarization of mitochondrial membrane potentials were hallmarks of the PD iPSCs. Further, a concomitant increase in glycolytic activity indicated a possible compensation for mitochondrial respiration. Elevated basal reactive oxygen species (ROS) and decreased catalase expression were also observed in the disease iPSCs. No change in autophagy was detected. These inceptive changes could be potential targets for early intervention of prodromal PD in the absence of disease-modifying therapies. However, additional investigations are crucial to delineate the cause-effect relationships of these observations.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}