Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-30DOI: 10.1016/j.celrep.2024.115116
Bei Zhou, Qin Zhao, Guofang Hou, Jing He, Nannan Sha, Ke Zheng, Hongyu Peng, Wang Wang, Yue Zhou, Tao Chen, Yuhui Jiang
{"title":"IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth.","authors":"Bei Zhou, Qin Zhao, Guofang Hou, Jing He, Nannan Sha, Ke Zheng, Hongyu Peng, Wang Wang, Yue Zhou, Tao Chen, Yuhui Jiang","doi":"10.1016/j.celrep.2024.115116","DOIUrl":"10.1016/j.celrep.2024.115116","url":null,"abstract":"<p><p>Inosine monophosphate dehydrogenase 2 (IMPDH2) is highly expressed in human cancers; however, its physiological relevance under growth signaling remains to be investigated. Here, we show that IMPDH2 serine 122 is phosphorylated by CDK1, and this modification attenuates the catalytic activity of IMPDH2 for IMP oxidation and simultaneously represses its allosteric modulation by purine nucleotides. Fibroblast growth factor receptor (FGFR) signaling activation triggers IMPDH2-Ser122 dephosphorylation mediated by protein phosphatase 2A (PP2A), which is dependent on FGFR3-mediated PPP2R1A-Tyr261 phosphorylation leading to PPP2CA-PPP2R1A-IMPDH2 interactions. In turn, Ser122 dephosphorylation positively modulates IMPDH2 activity and contributes to guanine nucleotide synthesis and purine homeostasis, thereby facilitating S-phase completion and cell proliferation. Accordingly, IMPDH2 dephosphorylation is implicated in FGFR activation-enhanced tumorigenesis, and the low level of IMPDH2-Ser122 phosphorylation predicts the poor prognosis of patients with colorectal cancer. These findings illustrate a regulatory mechanism of purine nucleotide production under FGFR signaling, in which the oncogenic effect of reinforced IMPDH2 activity is underscored.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115116"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Improved split prime editors enable efficient in vivo genome editing.","authors":"Rongwei Wei, Zhenxing Yu, Lihong Ding, Zhike Lu, Keyi Yao, Heng Zhang, Binglin Huang, Miao He, Lijia Ma","doi":"10.1016/j.celrep.2024.115144","DOIUrl":"10.1016/j.celrep.2024.115144","url":null,"abstract":"<p><p>Efficient prime editor (PE) delivery in vivo is critical for realizing its full potential in disease modeling and therapeutic correction. Although PE has been divided into two halves and delivered using dual adeno-associated viruses (AAVs), the editing efficiency at different gene loci varies among split sites. Furthermore, efficient split sites within Cas9 nickase (Cas9n) are limited. Here, we verified that 1115 (Asn) is an efficient split site when delivering PEs by dual AAVs. Additionally, we utilized a feature in which reverse transcriptase could be detached from the Cas9n and designed split sites in the first half of Cas9n. We found that split-PE-367 enabled high editing efficiency with Rma intein. To test the editing efficiency in vivo, split-ePE3-367 was packaged in AAV9 and achieved 17.5% precise editing in mice. Our findings establish an alternative split-PE architecture that enables robust editing efficiency, facilitating potential utility in disease modeling and correction.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115144"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chromatin-site-specific accessibility: A microtopography-regulated door into the stem cell fate.","authors":"Wenyan Zhou, Junxin Lin, Qianchun Wang, Xianliu Wang, Xudong Yao, Yiyang Yan, Wei Sun, Qiuwen Zhu, Xiaoan Zhang, Xiaozhao Wang, Baohua Ji, Hongwei Ouyang","doi":"10.1016/j.celrep.2024.115106","DOIUrl":"10.1016/j.celrep.2024.115106","url":null,"abstract":"<p><p>Biomaterials that mimic extracellular matrix topography are crucial in tissue engineering. Previous research indicates that certain biomimetic topography can guide stem cells toward multiple specific lineages. However, the mechanisms by which topographic cues direct stem cell differentiation remain unclear. Here, we demonstrate that microtopography influences nuclear tension in mesenchymal stem cells (MSCs), shaping chromatin accessibility and determining lineage commitment. On aligned substrates, MSCs exhibit high cytoskeletal tension along the fiber direction, creating anisotropic nuclear stress that opens chromatin sites for neurogenic, myogenic, and tenogenic genes via transcription factors like Nuclear receptor TLX (TLX). In contrast, random substrates induce isotropic nuclear stress, promoting chromatin accessibility for osteogenic and chondrogenic genes through Runt-related transcription factors (RUNX). Our findings reveal that aligned and random microtopographies direct site-specific chromatin stretch and lineage-specific gene expression, priming MSCs for distinct lineages. This study introduces a novel framework for understanding how topographic cues govern cell fate in tissue repair and regeneration.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115106"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-24DOI: 10.1016/j.celrep.2024.115120
Dillon P Boulton, Connor J Hughes, Valentina Vaira, Alessandro Del Gobbo, Alessandro Palleschi, Marco Locatelli, Etienne Danis, Masoom Raza, Andrew J Neumann, Stephen Connor Purdy, Raymundo Lerma, John Meshki, Heide L Ford, Rytis Prekeris, Colm Morrissey, M Cecilia Caino
{"title":"MIRO2 promotes cancer invasion and metastasis via MYO9B suppression of RhoA activity.","authors":"Dillon P Boulton, Connor J Hughes, Valentina Vaira, Alessandro Del Gobbo, Alessandro Palleschi, Marco Locatelli, Etienne Danis, Masoom Raza, Andrew J Neumann, Stephen Connor Purdy, Raymundo Lerma, John Meshki, Heide L Ford, Rytis Prekeris, Colm Morrissey, M Cecilia Caino","doi":"10.1016/j.celrep.2024.115120","DOIUrl":"10.1016/j.celrep.2024.115120","url":null,"abstract":"<p><p>Metastasis to vital organs remains the leading cause of cancer-related deaths, emphasizing an urgent need for actionable targets in advanced-stage cancer. The role of mitochondrial Rho GTPase 2 (MIRO2) in prostate cancer growth was recently reported; however, whether MIRO2 is important for additional steps in the metastatic cascade is unknown. Here, we show that knockdown of MIRO2 ubiquitously reduces tumor cell invasion in vitro and suppresses metastatic burden in prostate and breast cancer mouse models. Mechanistically, depletion of MIRO2's binding partner-unconventional myosin 9B (MYO9B)-reduces tumor cell invasion and phenocopies MIRO2 depletion, which in turn results in increased active RhoA. Furthermore, dual ablation of MIRO2 and RhoA fully rescues tumor cell invasion, and MIRO2 is required for MYO9B-driven invasion. Taken together, we show that MIRO2 supports invasion and metastasis through cooperation with MYO9B, underscoring a potential targetable pathway for patients with advanced disease.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115120"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-19DOI: 10.1016/j.celrep.2024.115078
Anne Bormann, Marek B Körner, Anne-Kristin Dahse, Marie S Gläser, Johanna Irmer, Vera Lede, Judith Alenfelder, Joris Lehmann, Daniella C N Hall, Michael Thane, Michael Schleyer, Evi Kostenis, Torsten Schöneberg, Marina Bigl, Tobias Langenhan, Dmitrij Ljaschenko, Nicole Scholz
{"title":"Intron retention of an adhesion GPCR generates 1TM isoforms required for 7TM-GPCR function.","authors":"Anne Bormann, Marek B Körner, Anne-Kristin Dahse, Marie S Gläser, Johanna Irmer, Vera Lede, Judith Alenfelder, Joris Lehmann, Daniella C N Hall, Michael Thane, Michael Schleyer, Evi Kostenis, Torsten Schöneberg, Marina Bigl, Tobias Langenhan, Dmitrij Ljaschenko, Nicole Scholz","doi":"10.1016/j.celrep.2024.115078","DOIUrl":"10.1016/j.celrep.2024.115078","url":null,"abstract":"<p><p>Adhesion G protein-coupled receptors (aGPCRs) are expressed in all organs and are involved in various mechanobiological processes. They are heavily alternatively spliced, forecasting an extraordinary molecular structural diversity. Here, we uncovered the existence of unconventional single-transmembrane (1TM)-containing ADGRL/Cirl proteins devoid of the conventional GPCR layout (i.e., the 7TM signaling unit) in Drosophila. These 1TM proteins are made as a result of intron retention and provide an N-terminal fragment that acts as an interactor to allow Gα<sub>o</sub>-dependent signaling through conventional 7TM-containing Cirl isoforms encoded by the same gene. This molecular mechanism determines sensory precision of neurons in response to mechanical stimulation in vivo. This action mode of aGPCR provides a promising entry point for experimental and therapeutic approaches to intervene in aGPCR signaling and implicates alternative splicing as a physiological strategy to express a given aGPCR together with its molecular interactor.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115078"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-20DOI: 10.1016/j.celrep.2024.115115
Jae Seung Lee, Mark Dittmar, Jesse Miller, Minghua Li, Kasirajan Ayyanathan, Max Ferretti, Jesse Hulahan, Kanupriya Whig, Zienab Etwebi, Trevor Griesman, David C Schultz, Sara Cherry
{"title":"Pressure to evade cell-autonomous innate sensing reveals interplay between mitophagy, IFN signaling, and SARS-CoV-2 evolution.","authors":"Jae Seung Lee, Mark Dittmar, Jesse Miller, Minghua Li, Kasirajan Ayyanathan, Max Ferretti, Jesse Hulahan, Kanupriya Whig, Zienab Etwebi, Trevor Griesman, David C Schultz, Sara Cherry","doi":"10.1016/j.celrep.2024.115115","DOIUrl":"10.1016/j.celrep.2024.115115","url":null,"abstract":"<p><p>SARS-CoV-2 emerged, and continues to evolve, to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling occurring only in bystander cells. How the virus continues to evolve in the face of innate responses has important consequences, but the pathways involved are incompletely understood. Here, we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons and, thus, permissivity to infection. Mechanistically, autophagy (mitophagy) genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, loss of autophagy increased MAVS and overcomes ORF9b-mediated antagonism. This has driven the evolution of SARS-CoV-2 to express more ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of mitophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115115"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway.","authors":"Fengzhen Cui, Shiyu Deng, Yan Fu, Tongtong Xu, Shuangshuang Bao, Siyi Wang, Yahang Lin, Xianghui Wang, Faming Zhao, Tingting Zhang, Shunqing Xu, Zhijun Zhang, Wanlu Li, Guo-Yuan Yang, Huanwen Tang, Jixian Wang, Xia Sheng, Yaohui Tang","doi":"10.1016/j.celrep.2024.115126","DOIUrl":"10.1016/j.celrep.2024.115126","url":null,"abstract":"<p><p>Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear. Here, we demonstrate that maternal exposure to MBP enhances neural stem cell (NSC) differentiation into astrocytes with highly expressed C3 and LCN2 in mouse offspring, resulting in increased synapse phagocytosis and cognitive dysfunction. Mechanistically, we find that MBP exposure activates the IRE1α/XBP1s (spliced XBP1) stress response pathway, which regulates key genes involved in astrocyte differentiation (SOX9 and ATF3) and reactivity (C3 and LCN2). Conditional knockout or pharmacological inhibition of IRE1α markedly inhibits NSC differentiation into astrocytes and astrocyte reactivity, attenuates synapse phagocytosis, and improves cognitive function. This phenotype is further recapitulated in a human brain organoid model. Together, these findings unveil the molecular mechanism underlying the neurodevelopmental deficits caused by a widespread environmental pollutant.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115126"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-06DOI: 10.1016/j.celrep.2024.115159
Nils A Koch, Benjamin W Corrigan, Michael Feyerabend, Roberto A Gulli, Michelle S Jimenez-Sosa, Mohamad Abbass, Julia K Sunstrum, Sara Matovic, Megan Roussy, Rogelio Luna, Samuel A Mestern, Borna Mahmoudian, Susheel Vijayraghavan, Hiroyuki Igarashi, Kartik S Pradeepan, William J Assis, J Andrew Pruszynski, Shreejoy Tripathy, Jochen F Staiger, Guillermo Gonzalez-Burgos, Andreas Neef, Stefan Treue, Stefan Everling, Wataru Inoue, Anmar Khadra, Julio C Martinez-Trujillo
{"title":"Spike frequency adaptation in primate lateral prefrontal cortex neurons results from interplay between intrinsic properties and circuit dynamics.","authors":"Nils A Koch, Benjamin W Corrigan, Michael Feyerabend, Roberto A Gulli, Michelle S Jimenez-Sosa, Mohamad Abbass, Julia K Sunstrum, Sara Matovic, Megan Roussy, Rogelio Luna, Samuel A Mestern, Borna Mahmoudian, Susheel Vijayraghavan, Hiroyuki Igarashi, Kartik S Pradeepan, William J Assis, J Andrew Pruszynski, Shreejoy Tripathy, Jochen F Staiger, Guillermo Gonzalez-Burgos, Andreas Neef, Stefan Treue, Stefan Everling, Wataru Inoue, Anmar Khadra, Julio C Martinez-Trujillo","doi":"10.1016/j.celrep.2024.115159","DOIUrl":"10.1016/j.celrep.2024.115159","url":null,"abstract":"<p><p>Cortical neurons in brain slices display intrinsic spike frequency adaptation (I-SFA) to constant current inputs, while extracellular recordings show extrinsic SFA (E-SFA) during sustained visual stimulation. Inferring how I-SFA contributes to E-SFA during behavior is challenging due to the isolated nature of slice recordings. To address this, we recorded macaque lateral prefrontal cortex (LPFC) neurons in vivo during a visually guided saccade task and in vitro in brain slices. Broad-spiking (BS) putative pyramidal cells and narrow-spiking (NS) putative inhibitory interneurons exhibit both E-SFA and I-SFA. Developing a data-driven hybrid circuit model comprising NS model neurons receiving BS input reveals that NS model neurons exhibit longer SFA than observed in vivo; however, adding feedforward inhibition corrects this in a manner dependent on I-SFA. Identification of this circuit motif shaping E-SFA in LPFC highlights the roles of both intrinsic and network mechanisms in neural activity underlying behavior.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115159"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-08DOI: 10.1016/j.celrep.2024.115180
Qian Yang, Ahmad Abdulla, Muhammad Farooq, Yoshihiro Ishikawa, Siqiong June Liu
{"title":"Emotional stress increases GluA2 expression and potentiates fear memory via adenylyl cyclase 5.","authors":"Qian Yang, Ahmad Abdulla, Muhammad Farooq, Yoshihiro Ishikawa, Siqiong June Liu","doi":"10.1016/j.celrep.2024.115180","DOIUrl":"10.1016/j.celrep.2024.115180","url":null,"abstract":"<p><p>Stress can alter behavior and contributes to psychiatric disorders by regulating the expression of the GluA2 AMPA receptor subunit. We have previously shown in mice that exposure to predator odor stress elevates GluA2 transcription in cerebellar molecular layer interneurons (MLIs), and MLI activity is required for fear memory consolidation. Here, we identified the critical involvement of adenylyl cyclase 5, in both the stress-induced increase in GluA2 in MLIs and the enhancement of fear memory. We found that noradrenaline release during predator odor stress activates AC5 and downstream PKA-CREB signaling. This pathway interacts synergistically with α1-adrenergic receptors to promote synaptic GluA2 expression in MLIs. At a behavioral level, predator odor stress potentiates associative fear memory, and this is abolished in AC5 knockout mice, suggesting that AC5-dependent plasticity is required for enhanced memory formation. Therefore, AC5 is a promising pharmacological target for preventing stress-enhanced fear memory.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115180"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-07DOI: 10.1016/j.celrep.2024.115178
Morgan G Stykel, Shehani V Siripala, Eric Soubeyrand, Carla L Coackley, Ping Lu, Suelen Camargo, Sharanya Thevasenan, Gerardo Balderas Figueroa, Raphaella W L So, Erica Stuart, Rachi Panchal, Elissavet-Kalliopi Akrioti, Jeffery T Joseph, Omid Haji-Ghassemi, Era Taoufik, Tariq A Akhtar, Joel C Watts, Scott D Ryan
{"title":"G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis.","authors":"Morgan G Stykel, Shehani V Siripala, Eric Soubeyrand, Carla L Coackley, Ping Lu, Suelen Camargo, Sharanya Thevasenan, Gerardo Balderas Figueroa, Raphaella W L So, Erica Stuart, Rachi Panchal, Elissavet-Kalliopi Akrioti, Jeffery T Joseph, Omid Haji-Ghassemi, Era Taoufik, Tariq A Akhtar, Joel C Watts, Scott D Ryan","doi":"10.1016/j.celrep.2024.115178","DOIUrl":"10.1016/j.celrep.2024.115178","url":null,"abstract":"<p><p>Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115178"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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