ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-17DOI: 10.1021/acschemneuro.4c00576
Dev Madhubala, Rosy Mahato, Kangkon Saikia, Aparup Patra, Pedro Alexandrino Fernandes, Arun Kumar, Mojibur R Khan, Ashis K Mukherjee
{"title":"Snake Venom-Inspired Novel Peptides Protect <i>Caenorhabditis elegans</i> against Paraquat-Induced Parkinson's Pathology.","authors":"Dev Madhubala, Rosy Mahato, Kangkon Saikia, Aparup Patra, Pedro Alexandrino Fernandes, Arun Kumar, Mojibur R Khan, Ashis K Mukherjee","doi":"10.1021/acschemneuro.4c00576","DOIUrl":"10.1021/acschemneuro.4c00576","url":null,"abstract":"<p><p>The <i>in vivo</i> protective mechanisms of two low-molecular-mass (∼1.4 kDa) novel custom peptides (CPs) against paraquat-induced neurodegenerative dysfunction in the <i>Caenorhabditis elegans</i> model were deciphered. CPs prevented the paraquat from binding to the nerve ring adjacent to the pharynx in <i>C. elegans</i> (wild-type) by stable and high-affinity binding to the tyrosine-protein kinase receptor CAM-1, resulting in significant inhibition of paraquat-induced toxicity by reducing the production of reactive oxygen species, mitochondrial membrane depolarization, and chemosensory dysfunction. The CPs inhibited paraquat-induced dopaminergic neuron degeneration and alpha-synuclein protein expression, the hallmarks of Parkinson's disease, in transgenic BZ555 and NL5901 strains of <i>C. elegans</i>. Transcriptomic, functional proteomics, and quantitative reverse transcription-polymerase chain reaction analyses show that CPs prevented the increased expression of the genes involved in the skn-1 downstream pathway, thereby restoring paraquat-mediated oxidative stress, apoptosis, and neuronal damage in <i>C. elegans</i>. The ability of CPs to repair paraquat-induced damage was demonstrated by a network of gene expression profiles, illustrating the molecular relationships between the regulatory proteins.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1275-1296"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646431","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-11DOI: 10.1021/acschemneuro.5c00060
Jasmine Jade Butler, Chloé Aman, Marion Rivalan, Aurélie Fitoussi, Sandrine Parrot, Françoise Dellu-Hagedorn, Philippe De Deurwaerdère
{"title":"Neurochemical Assessment of Tissue Levels of Neurotransmitters for Approximating Neurotransmitter System Connectivity.","authors":"Jasmine Jade Butler, Chloé Aman, Marion Rivalan, Aurélie Fitoussi, Sandrine Parrot, Françoise Dellu-Hagedorn, Philippe De Deurwaerdère","doi":"10.1021/acschemneuro.5c00060","DOIUrl":"10.1021/acschemneuro.5c00060","url":null,"abstract":"<p><p>The post-mortem measurement of tissue neurotransmitters is an interesting technique to address the gross biochemical activity. Its primary limitation is a lack of temporal resolution, although this is mitigated by enhanced spatial resolution, compared to <i>in vivo</i> methods. This neurochemical data is quantitative and requires no complex transformation, making it ideal to analyze neurochemical connectivity via the correlation of the biochemical signals between brain regions. These correlative approaches to quantitative measurements are fundamentally based on the variability of the data, an underdeveloped area of analysis in neurochemistry. One of the main reasons, as discussed in this Viewpoint, is that neurochemists recognize that variability in quantitative data stems not only from the biological variability, such as interindividual differences, but also from factors such as analytical devices. There are several ways to reduce variability caused by analytical and experimental biases through well-designed, precise protocols, allowing for the study of meaningful biological variability, such as interindividual differences between subjects.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1243-1246"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602960","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-17DOI: 10.1021/acschemneuro.4c00862
Mengke Jia, Chuanbo Wang, Jinfei Mei, Sajjad Ahmad, Muhammad Fahad Nouman, Hongqi Ai
{"title":"Identification and Characterization of the Structure and Size of Aβ42 Oligomers Targeting the Receptor FcγRIIb.","authors":"Mengke Jia, Chuanbo Wang, Jinfei Mei, Sajjad Ahmad, Muhammad Fahad Nouman, Hongqi Ai","doi":"10.1021/acschemneuro.4c00862","DOIUrl":"10.1021/acschemneuro.4c00862","url":null,"abstract":"<p><p>Kam and colleagues discovered that FcγRIIb can specifically bind to Aβ42 oligomers (AβOs). The N-terminal residues F4 and D7 of Aβ42, as well as the W115 residue in domain D2 of FcγRIIb, are involved in this binding. However, the specificity of the FcγRIIb receptor's binding sites for AβOs and their dependence on different AβO species, including dimers (D/D<sub>T</sub>), trimers (T/T<sub>T</sub>), tetramers (Te/Te<sub>T</sub>), and pentamers (P/P<sub>T</sub>) during both the primary (P1) and secondary nucleation phases (P2), remains unknown. To address this, we employed molecular dynamics (MD) simulations to investigate the interactions between the extracellular domains D1 and D2 (FDD) of FcγRIIb and AβOs of varying sizes in the two different phases. We discovered that three specific fragments (f1, f2, and f3) of domain D2 in FDD are the primary binding sites for AβO species. Furthermore, among AβOs of the same molecular weight, those from the P2 phase exhibit a stronger binding affinity for FDD than those from the P1 phase. The distinction is ascribed to the stronger dependence on the hydrophobic residues in the β1 and β2 regions for the binding of AβOs in P2 (including T<sub>T</sub>, Te<sub>T</sub>, and P<sub>T</sub>) than that (including D, Te, and P) in the P1 phase. In the P1 phase, these AβOs prefer to achieve binding to FDD through their N-terminal residues; however, by this, we identified that the species observed in Kam's experiment to bind FcγRIIb should probably be the tetrameric AβO (Te) in the P1 phase. Moreover, within both the P1 and P2 phases, we predicted that the trimeric AβO species in either the P1 or P2 phase is the strongest binding ligand for the FcγRIIb receptor. This study provides a comprehensive molecular perspective on the interaction between FcγRIIb and AβO in P2, which is of significant importance for the development of therapeutic strategies targeting Alzheimer's disease (AD) and autoimmune diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1335-1345"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646414","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-19DOI: 10.1021/acschemneuro.5c00092
Nilesh Gajanan Bajad, Gajendra T A, Khushboo Sharma, Madhu G Tapadia, Ashok Kumar, Sairam Krishnamurthy, Sushil Kumar Singh
{"title":"Development of Donor-Acceptor Architecture-Based Potential Theranostic Fluorescent Probes for Alzheimer's Disease.","authors":"Nilesh Gajanan Bajad, Gajendra T A, Khushboo Sharma, Madhu G Tapadia, Ashok Kumar, Sairam Krishnamurthy, Sushil Kumar Singh","doi":"10.1021/acschemneuro.5c00092","DOIUrl":"10.1021/acschemneuro.5c00092","url":null,"abstract":"<p><p>The cholinergic deficits and deposition of β-amyloid (Aβ) species are regarded as the key events contributing to the progression of Alzheimer's disease (AD). Herein, a series of novel donor-acceptor architecture-type potential theranostic agents were designed, synthesized, and evaluated for their potential against cholinesterase (ChE) enzymes and detection of Aβ species, which are primary targets in the development of therapeutics for AD. The optimal compound/probe <b>18</b> containing a benzothiazolium fluorophore with a bifunctional electron-donating <i>N</i>-aryl piperazine scaffold exhibited potent inhibitory activities against acetylcholinesterase (AChE; IC<sub>50</sub> = 0.172 ± 0.011 μM) and butyrylcholinesterase (BuChE; IC<sub>50</sub> = 1.376 ± 0.141 μM). Measurement of fluorescence properties showed that probe <b>18</b> exhibited emission maxima (λ<sub>em</sub>) of >610 nm in dimethyl sulfoxide (DMSO) and >590 nm in PBS, suitable for the fluorescence imaging. <i>In vitro</i> studies demonstrated a change in fluorescence characteristics and high binding affinities (<b>18</b>; <i>K</i><sub>d</sub> = 0.731 μM) upon binding with Aβ aggregates. The affinity of probe <b>18</b> toward Aβ aggregates was further observed in <i>elavGAL4 > UAS Aβ</i>, the <i>Drosophila</i> larval brain sections, using a fluorescence imaging technique. The <i>in vivo</i> acute oral toxicity evaluation indicated a safety profile of the lead probe 18. Moreover, <i>in vivo</i> behavioral studies including Y-maze and novel object recognition tests signified that the administration of compound <b>18</b> improved cognitive and spatial memory impairment at a dose of 10 and 20 mg/kg in the scopolamine-induced cognitive deficit model.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1388-1401"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661573","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-25DOI: 10.1021/acschemneuro.5c00075
Emanuel F Lopes, Alyssa M West, Jason L Locke, Katherine Holleran, Leighelle A Adrian, Monica H Dawes, Alyson M Curry, Harlie A McKelvey, Thomas Martin, Sara R Jones
{"title":"Morphine-Induced Antinociception Is Potentiated and Dopamine Elevations Are Inhibited by the Biased Kappa Opioid Receptor Agonist Triazole 1.1.","authors":"Emanuel F Lopes, Alyssa M West, Jason L Locke, Katherine Holleran, Leighelle A Adrian, Monica H Dawes, Alyson M Curry, Harlie A McKelvey, Thomas Martin, Sara R Jones","doi":"10.1021/acschemneuro.5c00075","DOIUrl":"10.1021/acschemneuro.5c00075","url":null,"abstract":"<p><p>Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1377-1387"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699063","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-24DOI: 10.1021/acschemneuro.5c00112
Ritu Soni, Vaishali Pankaj, Sudeep Roy, Amit Khairnar, Jigna Shah
{"title":"Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models.","authors":"Ritu Soni, Vaishali Pankaj, Sudeep Roy, Amit Khairnar, Jigna Shah","doi":"10.1021/acschemneuro.5c00112","DOIUrl":"10.1021/acschemneuro.5c00112","url":null,"abstract":"<p><p>Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. <i>In silico</i> studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The <i>in silico</i> studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1402-1417"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699064","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-13DOI: 10.1021/acschemneuro.4c00618
Giuseppe Tagliaferro, Maria Giulia Davighi, Francesca Clemente, Filippo Turchi, Marco Schiavina, Camilla Matassini, Andrea Goti, Amelia Morrone, Roberta Pierattelli, Francesca Cardona, Isabella C Felli
{"title":"Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives.","authors":"Giuseppe Tagliaferro, Maria Giulia Davighi, Francesca Clemente, Filippo Turchi, Marco Schiavina, Camilla Matassini, Andrea Goti, Amelia Morrone, Roberta Pierattelli, Francesca Cardona, Isabella C Felli","doi":"10.1021/acschemneuro.4c00618","DOIUrl":"10.1021/acschemneuro.4c00618","url":null,"abstract":"<p><p>Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs are often considered as undruggable because they lack defined binding pockets, which constitute the basis of drug discovery approaches. However, small molecules that interact with the intrinsically disordered state of α-synuclein, the protein linked to Parkinson's disease (PD), were recently identified and shown to act as chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations that code for GCase are among the most frequent genetic risk factors for PD. Following the \"dual-target\" approach, stating that one carefully designed molecule can, in principle, interfere with more than one target, we identified a pharmacological chaperone for GCase that interacts with the intrinsically disordered monomeric form of α-synuclein. This result opens novel avenues to be explored in the search for molecules that act on dual targets, in particular, with challenging targets such as IDPs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1251-1257"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622817","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":"New Insights on Protein Folding and Misfolding: Histidine Behaviors.","authors":"Yue Sun, Hu Shi","doi":"10.1021/acschemneuro.5c00167","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00167","url":null,"abstract":"<p><p>Protein folding is crucial as it determines the three-dimensional structure and function of proteins, which are essential for biological processes, while misfolding can lead to the formation of aggregates and dysfunctional proteins, often associated with diseases. Histidine behaviors have been identified as a contributing factor to protein folding and misfolding due to changes in net charge and the diverse orientations of N/N-H groups on imidazole rings. In this viewpoint, we discuss misfolding diseases, the fundamental principles of histidine behaviors, and relevant studies in this field. Our current study helps elucidate histidine behaviors and their impact on secondary structure and aggregation characteristics, offering new insights into the mechanisms of histidine-related protein folding and misfolding.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762626","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}
ACS Chemical NeurosciencePub Date : 2025-04-02Epub Date: 2025-03-17DOI: 10.1021/acschemneuro.5c00006
Mustafa Sertbas, Kutlu O Ulgen
{"title":"Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.","authors":"Mustafa Sertbas, Kutlu O Ulgen","doi":"10.1021/acschemneuro.5c00006","DOIUrl":"10.1021/acschemneuro.5c00006","url":null,"abstract":"<p><p>Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells by integrating single-cell RNA-seq data and global Human1 via a task-driven integrative network inference for tissues (tINIT) algorithm. Then, intercellular reactions among neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. This brain network was used in the prediction of metabolic alterations in glucose, ketone bodies, oxygen change, and reporter metabolites. Glucose supplementation increased the subsystems' activities in glycolysis, and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in gray and white matter microglia in multiple sclerosis (MS), respectively. Carbamoyl-phosphate was found to be the top reporter metabolite in primary progressive MS. Taken together, single and integrated iHumanBrain2690 metabolic networks help us elucidate complex metabolism in brain physiology and homeostasis in health and disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1346-1360"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646412","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":"Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.","authors":"Adam J Gatch, Feng Ding","doi":"10.1021/acschemneuro.5c00084","DOIUrl":"10.1021/acschemneuro.5c00084","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750247","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}