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A PKCη missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer’s disease PKCη错义突变增强高尔基定位信号，与隐性遗传家族性阿尔茨海默病有关

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-01 DOI: 10.1126/scisignal.adv0970

Maria Celeste Gauron, Dmitry Prokopenko, Sanghun Lee, Sarah A. Wolfe, Julian Hecker, Julian Willett, Mohammad Waqas, Gema Lordén, Yimin Yang, Joshua E. Mayfield, Isabel Castanho, Kristina Mullin, Sarah Morgan, Georg Hahn, Dawn L. Demeo, Winston Hide, Lars Bertram, Christoph Lange, Alexandra C. Newton, Rudolph E. Tanzi

{"title":"A PKCη missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer’s disease","authors":"Maria Celeste Gauron, Dmitry Prokopenko, Sanghun Lee, Sarah A. Wolfe, Julian Hecker, Julian Willett, Mohammad Waqas, Gema Lordén, Yimin Yang, Joshua E. Mayfield, Isabel Castanho, Kristina Mullin, Sarah Morgan, Georg Hahn, Dawn L. Demeo, Winston Hide, Lars Bertram, Christoph Lange, Alexandra C. Newton, Rudolph E. Tanzi","doi":"10.1126/scisignal.adv0970","DOIUrl":"10.1126/scisignal.adv0970","url":null,"abstract":"<div >The identification of Alzheimer’s disease (AD)–associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWASs) of AD have successfully identified previously unidentified targets but have almost exclusively used additive genetic models. Here, we performed a family-based GWAS of a recessive inheritance model using whole-genome sequencing from families affected by AD. We found an association between AD risk and the variant rs7161410, which is located in an intron of the <i>PRKCH</i> gene encoding protein kinase C eta (PKCη). In addition, a rare <i>PRKCH</i> missense mutation, K65R, was in linkage disequilibrium with rs7161410 and was present in homozygous carriers of the rs7161410 risk allele. In vitro analysis revealed that the catalytic rate, lipid dependence, and peptide substrate binding of the purified variant were indistinguishable from those of the wild-type kinase. However, cellular studies revealed that the K65R PKCη variant had reduced cytosolic activity and, instead, enhanced localization and signaling at the Golgi. Moreover, the K65R variant had altered interaction networks in transfected cells, particularly with proteins involved in Golgi processes such as vesicle transport. In human brain tissue, the AD-associated recessive genotype of rs7161410 was associated with increased expression of <i>PRKCH</i>, particularly in the amygdala. This association of aberrant PKCη signaling with AD and the insight into how its function is altered may lead to previously unidentified therapeutic targets for prevention and treatment.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 893","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525193","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}

引用次数: 0

Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s disease–linked LRRK2-mutant mice 激酶抑制剂治疗帕金森病相关lrrk2突变小鼠纹状体神经保护通路的恢复

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-01 DOI: 10.1126/scisignal.ads5761

Ebsy Jaimon, Yu-En Lin, Francesca Tonelli, Odetta Antico, Dario R. Alessi, Suzanne R. Pfeffer

{"title":"Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s disease–linked LRRK2-mutant mice","authors":"Ebsy Jaimon, Yu-En Lin, Francesca Tonelli, Odetta Antico, Dario R. Alessi, Suzanne R. Pfeffer","doi":"10.1126/scisignal.ads5761","DOIUrl":"10.1126/scisignal.ads5761","url":null,"abstract":"<div >Parkinson’s disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line–derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental inhibitor of LRRK2. Here, we found that dietary administration of MLi-2 to young LRRK2-mutant mice for 3 months restored primary cilia formation and Hedgehog signaling in both cholinergic and parvalbumin interneurons and astrocytes. The treatment also restored the Hedgehog-responsive expression of <i>Gdnf</i> and <i>Nrtn</i> in the neurons. Cilia were also restored on cholinergic neurons of the pedunculopontine nucleus, where their loss correlates with severity of motor impairment in patients. Furthermore, MLi-2 increased the density of fine striatal dopaminergic processes and decreased the amount of stress-associated Sonic Hedgehog RNA expression in nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in postmitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may therapeutically benefit patients.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 893","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525192","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}

引用次数: 0

Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway STIM2的缺失，而不是STIM1的缺失，通过代谢重编程和ATF4 ER应激途径驱动结直肠癌转移

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-24 DOI: 10.1126/scisignal.ads6550

Trayambak Pathak, J. Cory Benson, Martin T. Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A. Koltun, Gregory S. Yochum, Nadine Hempel, Mohamed Trebak

{"title":"Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway","authors":"Trayambak Pathak, J. Cory Benson, Martin T. Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A. Koltun, Gregory S. Yochum, Nadine Hempel, Mohamed Trebak","doi":"10.1126/scisignal.ads6550","DOIUrl":"10.1126/scisignal.ads6550","url":null,"abstract":"<div >The large amounts of calcium (Ca<sup>2+</sup>) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca<sup>2+</sup> store into the cytosol regulate many cellular functions, and altered ER Ca<sup>2+</sup> homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca<sup>2+</sup> sensors that synergistically activate cytosolic Ca<sup>2+</sup> influx through Orai channels to promote Ca<sup>2+</sup>-dependent changes in gene expression and ER Ca<sup>2+</sup> refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca<sup>2+</sup> content in a manner dependent on the ER Ca<sup>2+</sup> pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 892","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482393","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}

引用次数: 0

The lncRNA Gas5 is an activity-responsive scaffold that mediates cAMP-dependent synaptic plasticity lncRNA Gas5是一种活性反应支架，介导camp依赖性突触可塑性

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-24 DOI: 10.1126/scisignal.adn2044

Kaushik Chanda, Eddie Grinman, Kaylyn Clark, Abhishek Sadhu, Bindu Raveendra, Supriya Swarnkar, Sathyanarayanan V. Puthanveettil

{"title":"The lncRNA Gas5 is an activity-responsive scaffold that mediates cAMP-dependent synaptic plasticity","authors":"Kaushik Chanda, Eddie Grinman, Kaylyn Clark, Abhishek Sadhu, Bindu Raveendra, Supriya Swarnkar, Sathyanarayanan V. Puthanveettil","doi":"10.1126/scisignal.adn2044","DOIUrl":"10.1126/scisignal.adn2044","url":null,"abstract":"<div >Changes in the transcriptome are critical in shaping the structural plasticity of neurons, which underpins learning and long-term memory storage. Here, we explored the effect of two opposing, plasticity-associated pathways—cAMP second-messenger signaling and metabotropic glutamate receptor (mGluR1 and mGluR5) signaling—on the transcriptome in hippocampal neurons and how these pathways operate in distinct and coordinated manners to induce structural changes. Integration of transcriptome data and molecular pathway analysis identified central “hub” genes that were rapidly induced by cAMP and/or mGluR1/5 in hippocampal neurons. These included the long noncoding RNA (lncRNA) Gas5, whose expression was induced specifically by cAMP and which was targeted to dendrites by the kinesin motor protein KIF1A. In the dendrites, Gas5 interacted with various proteins and coding and noncoding RNAs associated with synaptic function and plasticity, and these interactions were altered by cAMP signaling. Gas5 interacted with the microRNA miR-26a-5p and sequestered it from several of its mRNA targets associated with neuronal function and whose translation was induced by cAMP. Gas5 was critical for excitatory synaptic transmission induced by cAMP but not those induced by mGluR1/5. Furthermore, Gas5 deficiency impaired dendritic branching and synapse morphology, and Gas5 abundance was decreased in the hippocampus of a mouse model of Alzheimer’s disease. Together, these findings provide insight into the transcriptional networks involved in synaptic plasticity and a lncRNA interactome that mediates dendritically localized regulation of excitatory synaptic transmission and neuronal architecture.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 892","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adn2044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GAGging cancer cell ferroptosis 窒息性癌细胞铁下垂

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-24 DOI: 10.1126/scisignal.adz8643

Annalisa M. VanHook

引用次数: 0

Amphiregulin contributes to neuropathic pain by enhancing glycolysis that stimulates histone lactylation in sensory neurons 双调节蛋白促进糖酵解，刺激感觉神经元组蛋白乳酸化，从而促进神经性疼痛

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-17 DOI: 10.1126/scisignal.adr9397

Yu-Tao Deng, Longfei Ma, Yixiao Mei, Ji-Shuai Wang, Xue-Hui Bai, Xuan-Jie Zheng, Jin-Xuan Ren, Da Zhong, Bing-Lin Zhou, Jia Dan, Xue Li, Yong-Jing Gao, Lina Yu, Min Yan, Bao-Chun Jiang

{"title":"Amphiregulin contributes to neuropathic pain by enhancing glycolysis that stimulates histone lactylation in sensory neurons","authors":"Yu-Tao Deng, Longfei Ma, Yixiao Mei, Ji-Shuai Wang, Xue-Hui Bai, Xuan-Jie Zheng, Jin-Xuan Ren, Da Zhong, Bing-Lin Zhou, Jia Dan, Xue Li, Yong-Jing Gao, Lina Yu, Min Yan, Bao-Chun Jiang","doi":"10.1126/scisignal.adr9397","DOIUrl":"10.1126/scisignal.adr9397","url":null,"abstract":"<div >The genesis of neuropathic pain after peripheral nerve injury is associated with changes in gene expression and cell metabolism in sensory neurons and the release of inflammatory cytokines. Here, we connected glycolytic metabolism induced by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) to histone lactylation and changes in gene expression that promote chronic neuropathic pain. In both male and female mice subjected to peripheral nerve injury, the mRNA and protein abundance of AREG and its receptor EGFR was increased in dorsal root ganglia (DRGs). AREG-EGFR signaling induced glycolytic metabolism by activating the kinase PKM2. An increase in the glycolytic byproduct lactate facilitated lactylation of the histone lysines H3K18 and H4K12 by the lactyltransferase p300 in DRG neurons. These modifications promoted the expression of genes encoding various proinflammatory and pronociceptive proteins that contribute to the development and maintenance of pain. Deletion or knockdown of AREG or pharmacologically inhibiting EGFR, PKM2, or p300 alleviated neuropathic pain in mice and attenuated the injury-induced hyperexcitability of nociceptive neurons. Targeting this metabolically driven epigenetic mechanism may be a way to treat neuropathic pain in patients.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 891","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309181","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}

引用次数: 0

Intracellular and nuclear CXCR4 signaling promotes terminal erythroblast differentiation and enucleation 细胞内和核内的CXCR4信号传导促进终端红母细胞分化和去核

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-17 DOI: 10.1126/scisignal.adt2678

Julia Christine Gutjahr, Elin Hub, Caroline Amy Anderson, Maryna Samus, Katharina Artinger, Esteban A. Gomez, Christoph Ratswohl, Natalie Wickli, Mandy Raum, Neil Dufton, Jesmond Dalli, Jemima J. Burden, Johan Duchene, Antal Rot

{"title":"Intracellular and nuclear CXCR4 signaling promotes terminal erythroblast differentiation and enucleation","authors":"Julia Christine Gutjahr, Elin Hub, Caroline Amy Anderson, Maryna Samus, Katharina Artinger, Esteban A. Gomez, Christoph Ratswohl, Natalie Wickli, Mandy Raum, Neil Dufton, Jesmond Dalli, Jemima J. Burden, Johan Duchene, Antal Rot","doi":"10.1126/scisignal.adt2678","DOIUrl":"10.1126/scisignal.adt2678","url":null,"abstract":"<div >The chemokine CXCL12 signals through its receptor CXCR4 to induce the migration of all leukocyte types and multiple other cell types. Here, we report that CXCR4 is expressed in mouse erythroblasts, the bone marrow erythroid precursors, in which it stimulates erythrocyte generation instead of chemotaxis. CXCR4 signaling promoted homeostatic erythroblast maturation and increased the expression of genes mainly involved in metabolism and chromatin organization. Consequently, genetic depletion of CXCR4 in erythroblasts inhibited late erythropoiesis and diminished bone marrow erythroid outputs. Binding of CXCL12 to CXCR4 stimulated its rapid endocytosis and translocation together with Gα<sub>i</sub> or phosphorylated β-arrestin1 into distinct intracellular compartments, including the nuclear envelope and nucleus. CXCL12 signaling promoted erythroblast elongation and the condensation and excentric positioning of nuclei and stimulated rapid perinuclear Ca<sup>2+</sup> transients that immediately preceded erythroblast enucleation. These findings highlight previously uncharacterized physiological roles for CXCR4 and bone marrow–derived CXCL12 in erythropoiesis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 891","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309182","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}

引用次数: 0

Sweet structures 甜蜜的结构

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-10 DOI: 10.1126/scisignal.adz5144

John F. Foley

引用次数: 0

Decoding extracellular matrix–lysosome cross-talk and its implications for neurodegenerative diseases 细胞外基质-溶酶体串扰的解码及其对神经退行性疾病的意义

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-10 DOI: 10.1126/scisignal.adt1936

Qinghu Yang, Huan Ma, Liang Yang, Ming Jiang, Xia Liu, Zhantao Bai

引用次数: 0

An in vivo screen identifies diverse domains that can act as force-dependent proteolytic switches for Notch activation 体内筛选确定了不同的结构域，这些结构域可以作为Notch激活的力依赖性蛋白水解开关

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-06-10 DOI: 10.1126/scisignal.adt4606

Frederick C. Baker, Jacob Harman, Trevor Jordan, Breana Walton, Amber Ajamu-Johnson, Rama F. Alashqar, Simran Bhikot, Gary Struhl, Paul D. Langridge

{"title":"An in vivo screen identifies diverse domains that can act as force-dependent proteolytic switches for Notch activation","authors":"Frederick C. Baker, Jacob Harman, Trevor Jordan, Breana Walton, Amber Ajamu-Johnson, Rama F. Alashqar, Simran Bhikot, Gary Struhl, Paul D. Langridge","doi":"10.1126/scisignal.adt4606","DOIUrl":"10.1126/scisignal.adt4606","url":null,"abstract":"<div >Notch proteins are single-pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages to release the cytosolic domains that function as transcription factors. Transmembrane ligands of the Delta/Serrate/LAG-2 (DSL) family activate Notch on neighboring cells by exerting a pulling force across the intercellular ligand-receptor bridge. This force is generated by Epsin-mediated endocytosis of the ligand into the signal-sending cell and results in the extracellular cleavage of the force-sensing negative regulatory region (NRR) of the receptor by an ADAM10 protease on the signal-receiving cell. Here, we used chimeric Notch and DSL proteins to screen for other domains that could function as ligand-dependent proteolytic switches in place of the NRR in the developing <i>Drosophila melanogaster</i> wing. The domains that could functionally substitute for the NRR in vivo derived from diverse source proteins, varied in sequence, and had different predicted structures, yet all depended on cleavage that was catalyzed by the <i>Drosophila</i> ADAM10 homolog Kuzbanian (Kuz) and stimulated by Epsin-mediated ligand endocytosis. The large sequence space of protein domains that can serve as force-sensing proteolytic switches suggests a widespread potential role for force-dependent, ADAM10-mediated proteolysis in other cell contact–dependent signaling mechanisms.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 890","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adt4606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0