Science Signaling最新文献

A sphingomyelin shield for flaviviruses 黄病毒的鞘磷脂保护膜

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-22 DOI: 10.1126/scisignal.aea6766

Wei Wong

引用次数: 0

Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet 心肌细胞中PTP1B的缺失改变了心脏代谢信号，以防止高脂肪饮食引起的心肌病

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-22 DOI: 10.1126/scisignal.adp6006

Yan Sun, Abhishek Kumar Mishra, Vasanth Chanrasekhar, Michaela Door, Chase W. Kessinger, Bing Xu, Peiyang Tang, Yunan Gao, Sarah Kamli-Salino, Katherine Nelson, Mirela Delibegovic, E. Dale Abel, Jonanthan A. Kirk, Maria I. Kontaridis

{"title":"Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet","authors":"Yan Sun, Abhishek Kumar Mishra, Vasanth Chanrasekhar, Michaela Door, Chase W. Kessinger, Bing Xu, Peiyang Tang, Yunan Gao, Sarah Kamli-Salino, Katherine Nelson, Mirela Delibegovic, E. Dale Abel, Jonanthan A. Kirk, Maria I. Kontaridis","doi":"10.1126/scisignal.adp6006","DOIUrl":"10.1126/scisignal.adp6006","url":null,"abstract":"<div >Cardiomyocytes (CMs) normally use fatty acid oxidation (FAO) as their primary energy source. In response to pathological stress, the substrate preference of CMs switches from FAO to glucose metabolism, leading to the development of heart failure. Obesity increases this pathological risk of cardiovascular disease. We focused on protein tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling, the abundance and activity of which are increased in brain, muscle, and adipose tissues in obese and/or diabetic animals and in obese human patients. We generated mice with CM-specific deficiency in PTP1B (<i>PTP1B<sup>fl/fl</sup>::ꭤMHC<sup>Cre/+</sup></i>) to investigate the CM-specific role of PTP1B in response to cardiac dysfunction induced by high-fat diet (HFD) feeding. Although no physiological or functional cardiac differences were observed at baseline, <i>PTP1B<sup>fl/fl</sup>::ꭤMHC<sup>Cre/+</sup></i> mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis induced by HFD feeding. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased FAO and lipolysis but reduced glucose metabolism. Furthermore, phosphoproteomics analyses and mechanistic studies identified an axis involving the kinases PKM2 and AMPK downstream of PTP1B in the heart, which collectively acted to promote FAO and suppress lipogenesis. Together, these results suggest that CM-specific deletion of PTP1B prevents a substrate switch from FAO to glucose metabolism, protecting the heart against the development of HFD-induced cardiac hypertrophy and dysfunction.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 896","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adp6006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681637","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

Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer 基于报告者的筛选确定RAS- raf突变是结直肠癌对活性状态RAS抑制剂耐药的驱动因素

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-22 DOI: 10.1126/scisignal.adr3738

Oleksandra Aust, Moritz R. T. Thiel, Eric Blanc, Mareen Lüthen, Viola Hollek, Rosario Astaburuaga-García, Bertram Klinger, Francisca Böhning, Alexandra Trinks, Dieter Beule, Björn Papke, David Horst, Nils Blüthgen, Christine Sers, Channing J. Der, Markus Morkel

{"title":"Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer","authors":"Oleksandra Aust, Moritz R. T. Thiel, Eric Blanc, Mareen Lüthen, Viola Hollek, Rosario Astaburuaga-García, Bertram Klinger, Francisca Böhning, Alexandra Trinks, Dieter Beule, Björn Papke, David Horst, Nils Blüthgen, Christine Sers, Channing J. Der, Markus Morkel","doi":"10.1126/scisignal.adr3738","DOIUrl":"10.1126/scisignal.adr3738","url":null,"abstract":"<div >Therapy-induced acquired resistance limits the clinical effectiveness of mutation-specific KRAS inhibitors in colorectal cancer (CRC). Here, we investigated whether broad-spectrum, active-state RAS inhibitors meet similar limitations. We found that KRAS-mutant CRC cell lines were sensitive to the RAS(ON) multiselective RAS inhibitor RMC-7977, given that treatment resulted in RAS-RAF-MEK-ERK pathway inhibition; halted proliferation; and, in some cases, induced apoptosis. RMC-7977 initially reduced the activity of a compartment-specific, dual-color reporter of ERK activity, with reporter reactivation emerging after long-term dose escalation. These drug-resistant cell populations exhibited distinct patterns of phospho-protein abundance, transcriptional activities, and genomic mutations, including a Y71H mutation in KRAS and an S257L mutation in RAF1. Transgenic expression of KRAS<sup>G13D, Y71H</sup> or RAF1<sup>S257L</sup> in drug-sensitive CRC cells induced resistance to RMC-7977. CRC cells that were resistant to RMC-7977 and harboring RAF1<sup>S257L</sup> exhibited synergistic sensitivity to concurrent inhibition of RAS and RAF. Our findings demonstrate the power of reporter-assisted screening together with single-cell analyses for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract the emergence of resistant cancer cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 896","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681636","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

Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib 髓细胞和淋巴细胞中癌蛋白TEL-ABL的自磷酸化赋予对变构ABL抑制剂阿西米尼的抗性

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-15

Serena Muratcioglu, Christopher A. Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T. Groves, Brian J. Druker, John Kuriyan

{"title":"Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib","authors":"Serena Muratcioglu, Christopher A. Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T. Groves, Brian J. Druker, John Kuriyan","doi":"","DOIUrl":"","url":null,"abstract":"<div >Chromosomal translocations that fuse <i>ABL1</i> to <i>BCR</i> or <i>TEL</i> cause human leukemias. In BCR-ABL and TEL-ABL fusion proteins, oligomerization and loss of an autoinhibitory myristoylation site in the SH3 domain of ABL lead to increased ABL tyrosine kinase activity. We assessed the ability of asciminib, an allosteric inhibitor of BCR-ABL that binds to the myristoyl-binding site in the ABL kinase domain, to inhibit these fusion proteins. Although the ABL components of the two fusion proteins have identical sequences, asciminib was much less effective against TEL-ABL than it was against BCR-ABL in cell-growth assays. In contrast, ATP-competitive tyrosine kinase inhibitors, such as imatinib and ponatinib, were equally effective against both fusion proteins. A helix in the ABL kinase domain that closes over bound asciminib was required for the sensitivity of BCR-ABL to the drug but had no effect on that of TEL-ABL, suggesting that the native autoinhibitory mechanism that asciminib engages in BCR-ABL is disrupted in TEL-ABL. Single-molecule microscopy demonstrated that BCR-ABL was mainly dimeric in cells, whereas TEL-ABL formed higher-order oligomers, which promoted trans-autophosphorylation, including of a regulatory phosphorylation site (Tyr<sup>89</sup>) in the SH3 domain of ABL. Nonphosphorylated TEL-ABL was intrinsically susceptible to inhibition by asciminib, but phosphorylation at Tyr<sup>89</sup> disassembled the autoinhibited conformation of ABL, thereby preventing asciminib from binding. Our results demonstrate that phosphorylation determines whether an ABL fusion protein is sensitive to allosteric inhibition.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 895","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635680","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

Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins 星形细胞RIPK3通过转录诱导蛇形蛋白在病毒性脑炎小鼠中发挥保护性抗炎活性

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-15

Marissa Lindman, Irving Estevez, Eduard Marmut, Evan M. DaPrano, Tsui-Wen Chou, Kimberly Newman, Colm Atkins, Natasha M. O’Brown, Brian P. Daniels

{"title":"Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins","authors":"Marissa Lindman, Irving Estevez, Eduard Marmut, Evan M. DaPrano, Tsui-Wen Chou, Kimberly Newman, Colm Atkins, Natasha M. O’Brown, Brian P. Daniels","doi":"","DOIUrl":"","url":null,"abstract":"<div >Flaviviruses pose a substantial threat to public health because of their ability to infect the central nervous system (CNS). Receptor-interacting protein kinase 3 (RIPK3) is a central coordinator that promotes neuroinflammation during viral infection of the CNS, a role that occurs independently of its canonical function in inducing necroptosis. Here, we used mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes promoted host survival during flavivirus encephalitis by limiting immune cell recruitment to the CNS. Despite inducing a proinflammatory transcriptional program, astrocytic RIPK3 restrained neuroinflammation by increasing the abundance of the protease inhibitor SerpinA3N, which preserved blood-brain barrier integrity, reduced leukocyte infiltration, and improved survival outcomes during flavivirus encephalitis. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 895","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635679","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

Mutant α-synuclein takes down autophagy 突变体α-synuclein抑制自噬

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-08 DOI: 10.1126/scisignal.aea2255

Leslie K. Ferrarelli

引用次数: 0

Evolution of growth factor signaling to the TSC complex to regulate mTORC1 生长因子信号传导至TSC复合体调控mTORC1的进化

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-08 DOI: 10.1126/scisignal.adw4165

Kun Wang, Sophie E. Lockwood, Brendan D. Manning

{"title":"Evolution of growth factor signaling to the TSC complex to regulate mTORC1","authors":"Kun Wang, Sophie E. Lockwood, Brendan D. Manning","doi":"10.1126/scisignal.adw4165","DOIUrl":"10.1126/scisignal.adw4165","url":null,"abstract":"<div >The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1 activation and its promotion of cell growth. Cryo–electron microscopy studies of the TSC protein complex have revealed that this phosphoregulation of TSC2 occurs almost exclusively on residues in loops that are outside of the evolutionarily conserved core structural elements and that did not resolve in these structures. These phosphorylation-rich unstructured loops evolved with metazoans, suggesting that the regulation of mTORC1 by diverse growth factors likely evolved with the emergence of complex body plans and diverse cell types to coordinate cell growth and metabolism within and across distinct tissues. Unlike the core structure of TSC2, these loops lack disease-associated missense mutations. These features suggest that the regulatory loops on TSC2 are more amenable to evolutionary changes that enable diverse signals to converge on the TSC protein complex to regulate mTORC1.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 894","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589981","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 MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function MDM2-p53轴调节norrin/ zzzzled4信号和血液-中枢神经系统屏障功能

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-07-08 DOI: 10.1126/scisignal.adt0983

Jacklyn Levey, Md. Abedin, Chi Zhang, Emmanuel Odame, Lingling Zhang, Ha-Neul Jo, Kaia Douglas, Heidi Roehrich, Zhe Chen, Harald J. Junge

{"title":"The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function","authors":"Jacklyn Levey, Md. Abedin, Chi Zhang, Emmanuel Odame, Lingling Zhang, Ha-Neul Jo, Kaia Douglas, Heidi Roehrich, Zhe Chen, Harald J. Junge","doi":"10.1126/scisignal.adt0983","DOIUrl":"10.1126/scisignal.adt0983","url":null,"abstract":"<div >Norrin-induced activation of β-catenin–dependent signaling through the receptor frizzled4 in endothelial cells (ECs) is essential for establishing and maintaining blood-CNS barrier function. We sought to determine how this pathway is modulated under stress or disease conditions. Specifically, we investigated the role of p53 in endothelial blood-CNS barriers because increased abundance of the transcription factor p53 in ECs correlates with leaky CNS blood vessels in type 2 diabetes. Using transcriptomic, cell-based, and mouse genetic approaches, we identified interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling. Mice with an EC-specific ablation of <i>Mdm2</i> showed decreased norrin/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and disrupted blood-retina barrier function, all of which were largely restored by concurrent <i>Trp53</i> deletion. Decreased norrin/frizzled4 signaling and inhibition of EC proliferation in response to p53 were associated with reduced expression of the condensin I complex component non-SMC condensin I complex subunit H (NCAPH). This study identifies a regulator of norrin/frizzled4 signaling and suggests that the clinical use of MDM2 inhibitors might impair the blood-CNS barrier. In addition, NCAPH may be a downstream effector of p53 in ECs and a candidate gene for familial exudative vitreoretinopathy (FEVR), which is caused by defects in norrin signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 894","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adt0983","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589982","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

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