ACS Chemical Neuroscience最新文献

{"title":"Ratiometric Imaging for Quantification of Elevated Ca2+ in Neurons Using Synthetic Low-Affinity Fluorescent Probe","authors":"Yuzuka Kuronuma,&nbsp;Yutaka Shindo,&nbsp;Rei Kumada,&nbsp;Akihiro Sakama,&nbsp;Daniel Citterio,&nbsp;Kotaro Oka* and Yuki Hiruta*,&nbsp;","doi":"10.1021/acschemneuro.4c0066810.1021/acschemneuro.4c00668","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00668https://doi.org/10.1021/acschemneuro.4c00668","url":null,"abstract":"<p >The availability of various calcium ion (Ca²⁺) fluorescent probes has contributed to revealing physiological events related to intracellular Ca²⁺. However, conventional probes face challenges for quantitatively and selectively visualizing high Ca²⁺ concentrations in cells induced by any stimuli, including biomolecules or electrical signal that disrupt Ca²⁺ homeostasis. In this report, we designed and synthesized a low-affinity ratiometric Ca²⁺ probe, <b>KLCA-Fura</b>, utilizing <i>o</i>-aminophenol-<i>N,N</i>-diacetate-<i>O</i>-methylene-methylphosphinate (APDAP) as a ligand, for which we recently demonstrated the suitability as a new low-affinity ligand for Ca²⁺. <b>KLCA-Fura</b> showed a blue shift in excitation wavelength with increasing Ca²⁺ concentration based on the intramolecular charge transfer (ICT). Its affinity for Ca²⁺ is lower than commercially available conventional Ca²⁺ probes. Furthermore, the selectivity for Ca²⁺ and the fluorescence intensity were considered sufficient to accurately detect Ca²⁺. The corresponding acetoxymethyl ester, <b>KLCA-FuraAM</b>, was synthesized for intracellular imaging and applied to Ca²⁺ quantification in neurons. <b>KLCA-FuraAM</b> enabled quantitative ratiometric monitoring of the two-step Ca²⁺ concentration increase induced by glutamate stimulation. While this two-step response was not clearly observed with a commercially available low-affinity ratiometric Ca²⁺ probe, Fura-FF, <b>KLCA-FuraAM</b> has demonstrated the potential to quantitatively visualize the behavior of high Ca²⁺ concentrations. The ratiometric low-affinity Ca²⁺ probe, <b>KLCA-Fura</b>, is expected to be a powerful tool for discovering new functions of Ca²⁺ in neurons.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"649–658 649–658"},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436234","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":"Acute Treatment with Salvianolic Acid A Produces Neuroprotection in Stroke Models by Inducing Excitatory Long-Term Synaptic Depression","authors":"Jinnan Li,&nbsp;Niya Wang,&nbsp;Qi Huang,&nbsp;Chunxiang Jiao,&nbsp;Weilin Liu,&nbsp;Chunxian Yang,&nbsp;Xun Tang,&nbsp;Rongrong Mao,&nbsp;Qixin Zhou*,&nbsp;Yuqiang Ding*,&nbsp;Baoci Shan* and Lin Xu*,&nbsp;","doi":"10.1021/acschemneuro.4c0072010.1021/acschemneuro.4c00720","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00720https://doi.org/10.1021/acschemneuro.4c00720","url":null,"abstract":"<p >Acute ischemic stroke (AIS) is a significant brain disease with a high mortality and disability rate. Additional therapies for AIS are urgently needed, and neuroplasticity mechanisms by agents are expected to be neuroprotective for AIS. As a major active component of Salvia miltiorrhiza, salvianolic acid A (SAA) has shown potential for preventing cardiovascular diseases. However, there is no evidence of the long-term effect of SAA on ischemic injury or its mechanism. Therefore, using rats and mice, we systematically investigated the impact of SAA on AIS from the perspective of neuroprotective and neuroplasticity. Here, we report that SAA induces a long-term depression (LTD)-like process in synapses. This antiexcitotoxicity action supports the SAA effect, including alleviating infarction and promoting blood circulation in photothrombosis and middle cerebral artery occlusion (MCAO) models. Furthermore, repeated positron emission tomography/computed tomography (PET/CT) imaging and behavioral assessments two months after AIS induction reveal that acute treatment of SAA promotes recovery from disrupted whole-brain glucose metabolism and impaired spatial memory. These data suggest that acute treatment of SAA is neuroprotective by improving long-term functional outcomes through a synaptic LTD-like process, providing a promising adjunct to current therapies to enable better recovery for AIS.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"659–672 659–672"},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436235","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":"Distinct Aggregation Behavior of N-Terminally Truncated Aβ4–42 Over Aβ1–42 in the Presence of Zn(II)","authors":"Chanju Na,&nbsp;Mingeun Kim,&nbsp;Gunhee Kim,&nbsp;Yuxi Lin,&nbsp;Young-Ho Lee,&nbsp;Wojciech Bal*,&nbsp;Eunju Nam* and Mi Hee Lim*,&nbsp;","doi":"10.1021/acschemneuro.4c0083110.1021/acschemneuro.4c00831","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00831https://doi.org/10.1021/acschemneuro.4c00831","url":null,"abstract":"<p >The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer’s disease (AD). Among the modifications observed in Aβ peptides, <i>N</i>-terminal truncation at Phe4, yielding Aβ_4–x, is highly prevalent in AD-affected brains and significantly alters Aβ’s metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ_4–x remains unexplored. Here, we report the distinct aggregation behavior of <i>N</i>-terminally truncated Aβ, specifically Aβ_4–42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ_1–42. Our findings reveal notable differences in the aggregation profiles of Aβ_4–42 and Aβ_1–42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"732–744 732–744"},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436173","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":"Determination of Trends Underlying Aspartic Acid Isomerization in Intact Proteins Reveals Unusually Rapid Isomerization of Tau","authors":"Thomas A. Shoff,&nbsp;Brielle Van Orman,&nbsp;Vivian C. Onwudiwe,&nbsp;Joseph C. Genereux and Ryan R. Julian*,&nbsp;","doi":"10.1021/acschemneuro.4c0072110.1021/acschemneuro.4c00721","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00721https://doi.org/10.1021/acschemneuro.4c00721","url":null,"abstract":"<p >Spontaneous chemical modifications in long-lived proteins can potentially change protein structure in ways that impact proteostasis and cellular health. For example, isomerization of aspartic acid interferes with protein turnover and is anticorrelated with cognitive acuity in Alzheimer’s disease. However, few isomerization rates have been determined for Asp residues in intact proteins. To remedy this deficiency, we used protein extracts from SH-SY5Y neuroblastoma cells as a source of a complex, brain-relevant proteome with no baseline isomerization. Cell lysates were aged <i>in vitro</i> to generate isomers, and extracted proteins were analyzed by data-independent acquisition (DIA) liquid chromatography–mass spectrometry (LC-MS). Although no Asp isomers were detected at day 0, isomerization increased over time and was quantifiable for 105 proteins by day 50. Data analysis revealed that the isomerization rate is influenced by both primary sequence and secondary structure, suggesting that steric hindrance and backbone rigidity modulate isomerization. Additionally, we examined lysates extracted under gentle conditions to preserve protein complexes and found that protein–protein interactions often slow isomerization. Base catalysis was explored as a means to accelerate Asp isomerization due to findings of accelerated asparagine deamidation. However, no substantial rate enhancement was found for isomerization, suggesting fundamental differences in acid–base chemistry. With an enhanced understanding of Asp isomerization in proteins in general, we next sought to better understand Asp isomerization in tau. <i>In vitro</i> aging of monomeric and aggregated recombinant tau revealed that tau isomerizes significantly faster than any similar protein within our data set, which is likely related to its correlation with cognition in Alzheimer’s disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"673–686 673–686"},"PeriodicalIF":4.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00721","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436034","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":"Synthesis and Evaluation of Benzylic 18F-Labeled N-Biphenylalkynyl Nipecotic Acid Derivatives for PET Imaging of GABA Transporter 1","authors":"Niels Knippenberg*,&nbsp;Matthias Bauwens,&nbsp;Alexandru Florea,&nbsp;Soma Rudi,&nbsp;Olaf Schijns,&nbsp;Govert Hoogland,&nbsp;Vincent Ornelis,&nbsp;Ronny Mohren,&nbsp;Michiel Vandenbosch,&nbsp;Felix M. Mottaghy,&nbsp;Thomas J. Cleij,&nbsp;Kasper Eersels,&nbsp;Bart van Grinsven and Hanne Diliën,&nbsp;","doi":"10.1021/acschemneuro.4c0078210.1021/acschemneuro.4c00782","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00782https://doi.org/10.1021/acschemneuro.4c00782","url":null,"abstract":"<p >As the main inhibitory neurotransmission system, the GABAergic system poses an interesting yet underutilized target for molecular brain imaging. While PET imaging of postsynaptic GABAergic neurons has been accomplished using radiolabeled benzodiazepines targeting the GABA_A receptor, the development of presynaptic radioligands targeting GABA transporter 1 (GAT1) has been unsuccessful thus far. Therefore, we developed a novel GAT1-addressing radioligand and investigated its applicability as a PET tracer in rodents. We selected a lipophilic nipecotic acid scaffold that is known to bind selectively to GAT1 as the basis for our radioligand. To obtain the desired candidate radiotracer <b>[</b>^<b>18</b><b>F]4</b>, ester-protected radioligands <b>[</b>^<b>18</b><b>F]11a-b</b> were synthesized through aliphatic nucleophilic radiofluorination of the respective bromo-precursors, after which chemical deprotection was attempted using various conditions. Because these deprotections were unsuccessful, it was evaluated whether the ethyl ester <b>[</b>^<b>18</b><b>F]11a</b> could function as a prodrug and afford the active radioligand <b>[</b>^<b>18</b><b>F]4</b> after <i>in vivo</i> ester hydrolysis by esterases. Unfortunately, PET imaging studies in a rat model using <b>[</b>^<b>18</b><b>F]11a</b> showed no brain uptake of the radiotracer. Instead, significant uptake of radioactivity was observed in the liver and bones, the latter being caused by radiodefluorination of the PET tracer. Since the PET tracer developed in this study was found to be unstable, further efforts should investigate the development of a more stable GAT1-addressing PET tracer without the potential labile benzyl fluoride moiety. Moreover, as the still intact fraction of the radiotracer did not cross the BBB, options other than the prodrug approach should be considered to increase the BBB permeability of future GAT1 radioligands.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"711–722 711–722"},"PeriodicalIF":4.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00782","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436045","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 Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach","authors":"Nathan P. Coles,&nbsp;Suzan Elsheikh,&nbsp;Agathe Quesnel,&nbsp;Lucy Butler,&nbsp;Claire Jennings,&nbsp;Chaimaa Tarzi,&nbsp;Ojodomo J. Achadu,&nbsp;Meez Islam,&nbsp;Karunakaran Kalesh,&nbsp;Annalisa Occhipinti,&nbsp;Claudio Angione,&nbsp;Jon Marles-Wright,&nbsp;David J. Koss,&nbsp;Alan J. Thomas,&nbsp;Tiago F. Outeiro,&nbsp;Panagiota S. Filippou and Ahmad A. Khundakar*,&nbsp;","doi":"10.1021/acschemneuro.4c0072610.1021/acschemneuro.4c00726","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00726https://doi.org/10.1021/acschemneuro.4c00726","url":null,"abstract":"<p >The aggregation of α-synuclein is crucial to the development of Lewy body diseases, including Parkinson’s disease and dementia with Lewy bodies. The aggregation pathway of α-synuclein typically involves a defined sequence of nucleation, elongation, and secondary nucleation, exhibiting prion-like spreading. This study employed Raman spectroscopy and machine learning analysis, alongside complementary techniques, to characterize the biomolecular changes during the fibrillation of purified recombinant wild-type α-synuclein protein. Monomeric α-synuclein was produced, purified, and subjected to a 7-day fibrillation assay to generate preformed fibrils. Stages of α-synuclein fibrillation were analyzed using Raman spectroscopy, with aggregation confirmed through negative staining transmission electron microscopy, mass spectrometry, and light scattering analyses. A machine learning pipeline incorporating principal component analysis and uniform manifold approximation and projection was used to analyze the Raman spectral data and identify significant peaks, resulting in differentiation between sample groups. Notable spectral shifts in α-synuclein were found in various stages of aggregation. Early changes (D1) included increases in α-helical structures (1303, 1330 cm^–1) and β-sheet formation (1045 cm^–1), with reductions in COO^– and CH₂ bond regions (1406, 1445 cm^–1). By D4, these structural shifts persist with additional β-sheet features. At D7, a decrease in β-sheet H-bonding (1625 cm^–1) and tyrosine ring breathing (830 cm^–1) indicates further structural stabilization, suggesting a shift from initial helical structures to stabilized β-sheets and aggregated fibrils. Additionally, alterations in peaks related to tyrosine, alanine, proline, and glutamic acid were identified, emphasizing the role of these amino acids in intramolecular interactions during the transition from α-helical to β-sheet conformational states in α-synuclein fibrillation. This approach offers insight into α-synuclein aggregation, enhancing the understanding of its role in Lewy body disease pathophysiology and potential diagnostic relevance.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"687–698 687–698"},"PeriodicalIF":4.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00726","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436044","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":"Subventricular Accumulation of Cu in the Aging Mouse Brain Does Not Associate with Anticipated Increases in Markers of Oxidative Stress","authors":"Ashley L. Hollings,&nbsp;Gaewyn C. Ellison,&nbsp;Meg Willans,&nbsp;Virginie Lam,&nbsp;Thomas Munyard,&nbsp;Aedena-Raquel Remy,&nbsp;Ryu Takechi,&nbsp;John C.L. Mamo,&nbsp;Sam Webb,&nbsp;Elizabeth J. New,&nbsp;Simon A. James,&nbsp;Chris Glover,&nbsp;Annaleise Klein,&nbsp;Jitraporn Vongsvivut,&nbsp;Daryl Howard and Mark J. Hackett*,&nbsp;","doi":"10.1021/acschemneuro.4c0032010.1021/acschemneuro.4c00320","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00320https://doi.org/10.1021/acschemneuro.4c00320","url":null,"abstract":"<p >Natural aging is associated with mild memory loss and cognitive decline, and age is the greatest risk factor for neurodegenerative diseases, such as Alzheimer’s disease. There is substantial evidence that oxidative stress is a major contributor to both natural aging and neurodegenerative disease, and coincidently, levels of redox active metals such as Fe and Cu are known to be elevated later in life. Recently, a pronounced age-related increase in Cu content has been reported to occur in mice and rats around a vital regulatory brain region, the subventricular zone of lateral ventricles. In our study herein, we have characterized lateral ventricle Cu content in a unique murine model of accelerated aging, senescence accelerated mouse-prone 8 (SAMP8) mice. Our results confirm an age-related increase in ventricle Cu content, consistent with the studies by others in wild-type mice and rats. Specifically, we observed Cu content to increase over the time frame 1 to 5 months and 5 to 9 months, but interestingly, no significant increase occurred between 9 and 12 months (although brain Cu content at 12 months was significantly elevated relative to 1 and 5 month-old animals). Despite the magnitude of Cu increase observed within the cells that comprise the subventricular zone of lateral ventricles (average 3 mM Cu, with isolated subcellular concentrations of 17 mM), we did not detect spectroscopic markers of thiol oxidation, protein aggregation, or lipid oxidation. The lack of evidence for oxidative stress in <i>ex vivo</i> animal tissue is in contrast to <i>in vitro</i> studies demonstrating that thiol, protein, and lipid oxidation is pronounced at these Cu concentrations. We suggest that our findings most likely indicate that the Cu ions in this brain region are sequestered in an unreactive form, possibly extended chains of Cu-thiolate complexes, which do not readily redox cycle in the aqueous cytosol. These results also appear to partially challenge the long-held view that age-related increases in brain metal content drive oxidative stress as we did not observe a concomitant association between age-related Cu increase and markers of oxidative stress, nor did we observe a net increase in Cu content between mice aged 9 and 12 months.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 3","pages":"292–302 292–302"},"PeriodicalIF":4.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143127654","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":"Blocking the p38 MAPK Signaling Pathway in the Rat Hippocampus Alleviates the Depressive-like Behavior Induced by Spinal Cord Injury","authors":"Zhiping Xie,&nbsp;Tianqi Xu,&nbsp;Jiwu Chen,&nbsp;Yongping Gui,&nbsp;Dengfeng Wan and Meihua Li*,&nbsp;","doi":"10.1021/acschemneuro.4c0041310.1021/acschemneuro.4c00413","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00413https://doi.org/10.1021/acschemneuro.4c00413","url":null,"abstract":"<p >Patients with spinal cord injury (SCI) may develop depression, which can affect their rehabilitation. However, the underlying mechanism of depression in SCI patients remains unclear. Previous studies have revealed increased p38 MAPK phosphorylation in the rat hippocampus after SCI, accompanied by depression-like behaviors. However, the role of the p38 MAPK signaling pathway in SCI-induced depression remains unclear. In this study, we used an aneurysm clip-induced rat SCI model to investigate whether p38 MAPK phosphorylation in the hippocampus is associated with depression-like behaviors in rats after SCI. Behavioral testing revealed that SB203580, a p38 MAPK signaling inhibitor, reduced depression-like behaviors. Western blotting and morphological analyses showed that SB203580 inhibited the activation of microglia and astrocytes in the hippocampus after SCI. Additionally, SB203580 reduced the expression of tumor necrosis factor α and increased p38 MAPK phosphorylation and the number of bromodeoxyuridine-positive cells in the hippocampus. These findings suggest that SB203580 can inhibit hippocampal remodeling and the neuroimmune response in the rat hippocampus after SCI. Therefore, the phosphorylation of p38 MAPK in the hippocampus plays a key role in the depression-like behaviors induced by SCI. The inhibition of p38 MAPK phosphorylation may represent a mechanism to protect against hippocampal injury induced by SCI.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"595–603 595–603"},"PeriodicalIF":4.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436043","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":"Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant","authors":"Zeynep Nur Cinviz,&nbsp; and ,&nbsp;Ozge Sensoy*,&nbsp;","doi":"10.1021/acschemneuro.4c0063010.1021/acschemneuro.4c00630","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00630https://doi.org/10.1021/acschemneuro.4c00630","url":null,"abstract":"<p >Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkin^S167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 3","pages":"417–427 417–427"},"PeriodicalIF":4.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143127289","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":"m6A Demethylase FTO-Mediated Upregulation of BAP1 Induces Neuronal Ferroptosis via the p53/SLC7A11 Axis in the MPP+/MPTP-Induced Parkinson’s Disease Model","authors":"Zhengyu Li,&nbsp;Xin Chen,&nbsp;Wenwen Xiang,&nbsp;Ting Tang and Li Gan*,&nbsp;","doi":"10.1021/acschemneuro.4c0062010.1021/acschemneuro.4c00620","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00620https://doi.org/10.1021/acschemneuro.4c00620","url":null,"abstract":"<p ><i>Background</i>: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. <i>Methods</i>: A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP⁺. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe²⁺ were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. <i>Results</i>: SK-N-SH cells treated with MPP⁺ showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP⁺-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. <i>Conclusion</i>: m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 3","pages":"405–416 405–416"},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143127426","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}