Science Advances最新文献_第6页

In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer 体内功能筛选揭示 KEAP1 缺失是小细胞肺癌化疗耐药性的驱动因素

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adq7084

Lauren Brumage, Scott Best, Daniel S. Hippe, Eli Grunblatt, Pritha Chanana, Feinan Wu, Myung Chang Lee, Zhe Ying, Ali Ibrahim, Jae Heun Chung, Anna Vigil, Jackson Fatherree, Slobodan Beronja, Patrick Paddison, Lucas Sullivan, Barzin Nabet, David MacPherson

{"title":"In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer","authors":"Lauren Brumage, Scott Best, Daniel S. Hippe, Eli Grunblatt, Pritha Chanana, Feinan Wu, Myung Chang Lee, Zhe Ying, Ali Ibrahim, Jae Heun Chung, Anna Vigil, Jackson Fatherree, Slobodan Beronja, Patrick Paddison, Lucas Sullivan, Barzin Nabet, David MacPherson","doi":"10.1126/sciadv.adq7084","DOIUrl":"10.1126/sciadv.adq7084","url":null,"abstract":"<div >Exquisitely chemosensitive initially, small cell lung cancer (SCLC) exhibits dismal outcomes owing to rapid transition to chemoresistance. Elucidating the genetic underpinnings has been challenging owing to limitations with cellular models. As SCLC patient-derived xenograft (PDX) models mimic therapeutic responses, we perform genetic screens in chemosensitive PDX models to identify drivers of chemoresistance. cDNA overexpression screens identify <i>MYC</i>, <i>MYCN</i>, and <i>MYCL</i>, while CRISPR deletion screens identify <i>KEAP1</i> loss as driving chemoresistance. Deletion of <i>KEAP1</i> switched a chemosensitive SCLC PDX model to become chemoresistant and resulted in sensitivity to inhibition of glutamine metabolism. Data from the IMpower133 clinical trial revealed ~6% of patients with extensive-stage SCLC exhibit <i>KEAP1</i> genetic alterations, with activation of a KEAP1/NRF2 transcriptional signature associated with reduced survival upon chemotherapy treatment. While roles for KEAP1/NRF2 have been unappreciated in SCLC, our genetic screens revealed KEAP1 loss as a driver of chemoresistance, while patient genomic analyses demonstrate clinical importance.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq7084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conservation impacts and hidden actions in a randomized controlled trial of a marine pay-to-release program 海洋付费释放计划的随机对照试验中的保护影响和隐藏行为

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adr1000

Hollie Booth, Thomas Pienkowski, M Said Ramdlan, Kusuma Banda Naira, Muhsin, E. J. Milner-Gulland, Luky Adrianto, Paul J. Ferraro

{"title":"Conservation impacts and hidden actions in a randomized controlled trial of a marine pay-to-release program","authors":"Hollie Booth, Thomas Pienkowski, M Said Ramdlan, Kusuma Banda Naira, Muhsin, E. J. Milner-Gulland, Luky Adrianto, Paul J. Ferraro","doi":"10.1126/sciadv.adr1000","DOIUrl":"10.1126/sciadv.adr1000","url":null,"abstract":"<div >Incentive payments could cost-effectively and equitably achieve biodiversity conservation goals but could also trigger unintended countervailing actions. Here, we report on a preregistered, randomized controlled trial of a pay-to-release program among small-scale, Indonesian fishing vessels for the release of two critically endangered marine taxa from fishing gear: hammerhead sharks and wedgefish. A conventional monitoring approach, which quantifies impacts based on conservation-relevant actions (i.e., numbers of live releases), implies that the program was successful: a 71 and 4% reduction in wedgefish and hammerhead shark mortality, respectively. The experimental data, however, imply that the pay-to-release program also induced some vessels to increase their catch, thereby decreasing wedgefish mortality by only 25% [confidence interval (CI): −49 to 10%] and increasing hammerhead mortality by 44% (CI: 8 to 92%). Our results do not imply that pay-to-release programs cannot work but rather demonstrate the complexity of designing incentive-based conservation programs and the importance of piloting them using experimental designs before scaling up.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr1000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer 急性BRCAness诱导和AR通路阻断通过CDK12/7/9降解增强PARP抑制剂在前列腺癌中的敏感性

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adu0847

Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P. Balk, Adam S. Kibel, Li Jia

{"title":"Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer","authors":"Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P. Balk, Adam S. Kibel, Li Jia","doi":"10.1126/sciadv.adu0847","DOIUrl":"10.1126/sciadv.adu0847","url":null,"abstract":"<div >Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained “BRCAness” state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent antitumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu0847","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial distribution of fishmeal and fish oil factories around the globe 全球鱼粉和鱼油工厂的空间分布

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adr6921

Lauren A. Shea, Colette C. C. Wabnitz, William W. L. Cheung, Daniel Pauly, U. Rashid Sumaila

{"title":"Spatial distribution of fishmeal and fish oil factories around the globe","authors":"Lauren A. Shea, Colette C. C. Wabnitz, William W. L. Cheung, Daniel Pauly, U. Rashid Sumaila","doi":"10.1126/sciadv.adr6921","DOIUrl":"10.1126/sciadv.adr6921","url":null,"abstract":"<div >Fishmeal and fish oil (FMFO) are critical inputs for the compound aquatic feeds sustaining the fed aquaculture sector, yet there is limited publicly available information on the location of FMFO production factories around the globe. This makes it difficult to assess the environmental, social, and economic impacts of individual factories and the industry’s footprint as a whole. To fill this knowledge gap, we compiled location data for FMFO factories across 63 producing countries. We identified 506 factories owned and/or operated by 413 companies. We provide an open-source database that includes FMFO factory locations, company names, and raw material types. This study offers a first look at the spatial distribution of the FMFO industry and serves as a valuable resource for marine resource managers and policymakers. Knowing the locations of factories and where FMFO production is concentrated can inform the development of cooperative national and international policies to ensure environmentally and socially responsible standards.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr6921","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3D bioprinting of collagen-based high-resolution internally perfusable scaffolds for engineering fully biologic tissue systems 基于胶原蛋白的高分辨率内部可灌注支架的3D生物打印，用于工程全生物组织系统

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adu5905

Daniel J. Shiwarski, Andrew R. Hudson, Joshua W. Tashman, Ezgi Bakirci, Samuel Moss, Brian D. Coffin, Adam W. Feinberg

{"title":"3D bioprinting of collagen-based high-resolution internally perfusable scaffolds for engineering fully biologic tissue systems","authors":"Daniel J. Shiwarski, Andrew R. Hudson, Joshua W. Tashman, Ezgi Bakirci, Samuel Moss, Brian D. Coffin, Adam W. Feinberg","doi":"10.1126/sciadv.adu5905","DOIUrl":"10.1126/sciadv.adu5905","url":null,"abstract":"<div >Organ-on-a-chip and microfluidic systems have improved the translational relevance of in vitro systems; however, current manufacturing approaches impart limitations on materials selection, non-native mechanical properties, geometric complexity, and cell-driven remodeling into functional tissues. Here, we three-dimensionally (3D) bioprint extracellular matrix (ECM) and cells into collagen-based high-resolution internally perfusable scaffolds (CHIPS) that integrate with a vascular and perfusion organ-on-a-chip reactor (VAPOR) to form a complete tissue engineering platform. We improve the fidelity of freeform reversible embedding of suspended hydrogels (FRESH) bioprinting to produce a range of CHIPS designs fabricated in a one-step process. CHIPS exhibit size-dependent permeability of perfused molecules into the surrounding scaffold to support cell viability and migration. Lastly, we implemented multi-material bioprinting to control 3D spatial patterning, ECM composition, cellularization, and material properties to create a glucose-responsive, insulin-secreting pancreatic-like CHIPS with vascular endothelial cadherin<sup>+</sup> vascular-like networks. Together, CHIPS and VAPOR form a platform technology toward engineering full organ-scale function for disease modeling and cell replacement therapy.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu5905","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Input-driven dynamics for robust memory retrieval in Hopfield networks Hopfield 网络中稳健记忆检索的输入驱动动力学

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adu6991

Simone Betteti, Giacomo Baggio, Francesco Bullo, Sandro Zampieri

{"title":"Input-driven dynamics for robust memory retrieval in Hopfield networks","authors":"Simone Betteti, Giacomo Baggio, Francesco Bullo, Sandro Zampieri","doi":"10.1126/sciadv.adu6991","DOIUrl":"10.1126/sciadv.adu6991","url":null,"abstract":"<div >The Hopfield model provides a mathematical framework for understanding the mechanisms of memory storage and retrieval in the human brain. This model has inspired decades of research on learning and retrieval dynamics, capacity estimates, and sequential transitions among memories. Notably, the role of external inputs has been largely underexplored, from their effects on neural dynamics to how they facilitate effective memory retrieval. To bridge this gap, we propose a dynamical system framework in which the external input directly influences the neural synapses and shapes the energy landscape of the Hopfield model. This plasticity-based mechanism provides a clear energetic interpretation of the memory retrieval process and proves effective at correctly classifying mixed inputs. Furthermore, we integrate this model within the framework of modern Hopfield architectures to elucidate how current and past information are combined during the retrieval process. Last, we embed both the classic and the proposed model in an environment disrupted by noise and compare their robustness during memory retrieval.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu6991","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intratumoral self-assembly of renal-clearable gold nanoparticles as precise photothermal nanomedicine for liver tumor therapy 可清除肾脏的金纳米粒子的瘤内自组装作为精确的光热纳米药物用于肝脏肿瘤治疗

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adw7032

Gangqiang Yuan, Xiaoxi Luo, Kui He, Yue Tan, Caiming Luo, Ben Liu, Yidan Sun, Jinbin Liu

{"title":"Intratumoral self-assembly of renal-clearable gold nanoparticles as precise photothermal nanomedicine for liver tumor therapy","authors":"Gangqiang Yuan, Xiaoxi Luo, Kui He, Yue Tan, Caiming Luo, Ben Liu, Yidan Sun, Jinbin Liu","doi":"10.1126/sciadv.adw7032","DOIUrl":"10.1126/sciadv.adw7032","url":null,"abstract":"<div >Noninvasive photothermal therapy (PTT) for cancer with photothermal agents (PTAs) has recently achieved success in both preclinical and clinical trials. However, traditional PTAs tend to nonspecifically accumulate in normal liver tissue, hampering their use in PTT of liver tumors. By taking advantage of extremely low liver accumulation from ultrasmall renal-clearable gold nanoparticles (AuNPs), we report a biosafe therapeutic PTT strategy to treat liver tumors precisely through the intratumoral self-assembly of renal-clearable AuNPs at the tumor site via host-guest interactions. After active tumor targeting from the host AuNPs functionalized with both cyclo (Arg-Gly-Asp-<span>d</span>-Phe-Cys) and cyclodextrin, the guest AuNPs functionalized with both pH-responsive doxorubicin and adamantane are designed to precisely trigger intratumoral self-assembly, enhancing both PTT and chemotherapy toward the liver tumor microenvironment. This smart design principle generates a precise therapeutic action toward liver tumors without causing any noticeable heating effect or damage to the surrounding normal liver tissue.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adw7032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies 人类抗体识别的流感 H1 和 H3 血凝素上的保守位点

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adu9140

Daniel P. Maurer, Mya Vu, Ana Sofia Ferreira Ramos, Haley L. Dugan, Paul Khalife, James C. Geoghegan, Laura M. Walker, Goran Bajic, Aaron G. Schmidt

{"title":"Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies","authors":"Daniel P. Maurer, Mya Vu, Ana Sofia Ferreira Ramos, Haley L. Dugan, Paul Khalife, James C. Geoghegan, Laura M. Walker, Goran Bajic, Aaron G. Schmidt","doi":"10.1126/sciadv.adu9140","DOIUrl":"10.1126/sciadv.adu9140","url":null,"abstract":"<div >Monoclonal antibodies (mAbs) targeting the influenza hemagglutinin (HA) can be used as prophylactics or templates for next-generation vaccines. Here, we isolated broad, subtype-neutralizing mAbs from human B cells recognizing the H1 or H3 HA “head” and a mAb engaging the conserved stem. The H1 mAbs bind the lateral patch epitope on HAs from 1933 to 2021 and a prepandemic swine H1N1 virus. We improved neutralization potency using directed evolution toward a contemporary H1 HA. Deep mutational scanning of four antigenically distinct H1N1 viruses identified potential viral escape pathways. For the H3 mAbs, we used cryo–electron microscopy to define their epitopes: One mAb binds the side of the HA head, accommodating the N133 glycan and a pocket underneath the receptor binding site; the other mAb recognizes an HA stem epitope that partially overlaps with previously characterized mAbs but with distinct antibody variable genes. Collectively, these mAbs identify conserved sites recognized by broadly-reactive mAbs that may be elicited by next-generation vaccines.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu9140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Climate-induced shifts in sulfate dynamics regulate anaerobic methane oxidation in a coastal wetland 气候引起的硫酸盐动态变化调节了沿海湿地厌氧甲烷氧化

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.ads6093

Jaehyun Lee, Yerang Yang, Hojeong Kang, Genevieve L. Noyce, J. Patrick Megonigal

{"title":"Climate-induced shifts in sulfate dynamics regulate anaerobic methane oxidation in a coastal wetland","authors":"Jaehyun Lee, Yerang Yang, Hojeong Kang, Genevieve L. Noyce, J. Patrick Megonigal","doi":"10.1126/sciadv.ads6093","DOIUrl":"10.1126/sciadv.ads6093","url":null,"abstract":"<div >Anaerobic methane oxidation (AMO) is a key microbial pathway that mitigates methane emissions in coastal wetlands, but the response of AMO to changing global climate remains poorly understood. Here, we assessed the response of AMO to climate change in a brackish coastal wetland using a 5-year field manipulation of warming and elevated carbon dioxide (<i>e</i>CO<sub>2</sub>). Sulfate (SO<sub>4</sub><sup>2−</sup>)–dependent AMO (S-DAMO) was the predominant AMO process at our study site due to tidal inputs of SO<sub>4</sub><sup>2−</sup>. However, SO<sub>4</sub><sup>2−</sup> dynamics responded differently to the treatments; warming reduced SO<sub>4</sub><sup>2−</sup> concentration by enhancing SO<sub>4</sub><sup>2−</sup> reduction, while <i>e</i>CO<sub>2</sub> increased SO<sub>4</sub><sup>2−</sup> concentration by enhancing SO<sub>4</sub><sup>2−</sup> regeneration. S-DAMO rates mirrored these trends, with warming decreasing S-DAMO rates and <i>e</i>CO<sub>2</sub> stimulating them. These findings underscore the potential of climate change to alter soil AMO activities through changing SO<sub>4</sub><sup>2−</sup> dynamics, highlighting the need to incorporate these processes in predictive models for more accurate representations of coastal wetland methane dynamics.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads6093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons 细胞内 ATP 的缺失会影响哺乳动物神经元的轴质粘度和病理性蛋白质聚集

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-04-23 DOI: 10.1126/sciadv.adq6077

Laurent Guillaud, Anna Garanzini, Sarah Zakhia, Sandra De la Fuente, Dimitar Dimitrov, Susan Boerner, Marco Terenzio

{"title":"Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons","authors":"Laurent Guillaud, Anna Garanzini, Sarah Zakhia, Sandra De la Fuente, Dimitar Dimitrov, Susan Boerner, Marco Terenzio","doi":"10.1126/sciadv.adq6077","DOIUrl":"10.1126/sciadv.adq6077","url":null,"abstract":"<div >Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell–derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 17","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq6077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0