Life Science Alliance最新文献

Trans-scale live-imaging of an E5.5 mouse embryo using incubator-type biaxial light-sheet microscopy. 利用培养型双轴光片显微镜对E5.5小鼠胚胎进行跨尺度实时成像。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-15 Print Date: 2025-03-01 DOI: 10.26508/lsa.202402839

Go Shioi, Tomonobu M Watanabe, Junichi Kaneshiro, Yusuke Azuma, Shuichi Onami

{"title":"Trans-scale live-imaging of an E5.5 mouse embryo using incubator-type biaxial light-sheet microscopy.","authors":"Go Shioi, Tomonobu M Watanabe, Junichi Kaneshiro, Yusuke Azuma, Shuichi Onami","doi":"10.26508/lsa.202402839","DOIUrl":"10.26508/lsa.202402839","url":null,"abstract":"During mouse embryonic development, the embryonic day (E) 5.5 stage represents a crucial period for the formation of the primitive body axis, where the symmetry breaking of cellular states influences the multicellular system. Elucidating the detailed mechanisms of this process necessitates a trans-layered dynamic observation of the embryo and all internal cells. In this report, we present our success in achieving in-toto single-cell observation in a whole hemisphere of an E5.5 embryo for 12 h, using a newly developed incubator-type biaxial light-sheet microscope. To achieve the success, we optimized our microscope system, including an incubator for culture stability, and refining the observation protocol to reduce phototoxicity. Our key discovery is that the scan speed during light-sheet formation plays a critical role in reducing phototoxicity, rather than the irradiation intensity or the interval time between frames. This innovative system not only enabled in-toto single-cell tracking but also led to the discovery of the abrupt shrinking of embryos whose contractile center was located at the extraembryonic ectoderm during monotonous growth up to the E6.5 stage.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress. 转录因子EB （TFEB）活性增加TNBC干细胞对代谢应激的抗性。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-15 Print Date: 2025-03-01 DOI: 10.26508/lsa.202302259

Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg

{"title":"Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.","authors":"Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg","doi":"10.26508/lsa.202302259","DOIUrl":"10.26508/lsa.202302259","url":null,"abstract":"Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia. UNC119调节原代T细胞和T急性淋巴细胞白血病中的T细胞受体信号。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-15 Print Date: 2025-03-01 DOI: 10.26508/lsa.202403066

Youhani Samarakoon, Tamas Yelland, Esther Garcia-Gonzalez, Amauri da Silva Justo Junior, Mahnoor Mahmood, Anand Manoharan, Shaun Patterson, Valentina Serafin, Payam A Gammage, Sandra Marmiroli, Christina Halsey, Shehab Ismail, Edward W Roberts

{"title":"UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.","authors":"Youhani Samarakoon, Tamas Yelland, Esther Garcia-Gonzalez, Amauri da Silva Justo Junior, Mahnoor Mahmood, Anand Manoharan, Shaun Patterson, Valentina Serafin, Payam A Gammage, Sandra Marmiroli, Christina Halsey, Shehab Ismail, Edward W Roberts","doi":"10.26508/lsa.202403066","DOIUrl":"10.26508/lsa.202403066","url":null,"abstract":"T-cell receptor recognition of cognate peptide-MHC leads to the formation of signalling domains and the immunological synapse. Because of the close membrane apposition, there is rapid exclusion of CD45, and therefore LCK activation. Much less is known about whether spatial regulation of the intracellular face dictates LCK activity and TCR signal transduction. Moreover, as LCK is a driver in T acute lymphocytic leukaemia, it is important to understand its regulation. Here, we demonstrate a direct role of the ciliary protein UNC119 in trafficking LCK to the immunological synapse. Inhibiting UNC119 reduces localisation of LCK without impairing LCK phosphorylation and reduces T-cell receptor signal transduction. Although important for initial LCK reorganisation, activated CD8+ T cells retained their ability to kill target tumour cells when UNC119 was inhibited. UNC119 was also needed to sustain proliferation in patient-derived T-ALL cells. UNC119 may therefore represent a novel therapeutic target in T acute lymphocytic leukaemia, which alters the subcellular localisation of LCK in T acute lymphocytic leukaemia cells but preserves the function of existing cytotoxic lymphocytes.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Divergent destinies: insights into the molecular mechanisms underlying EPI and PE fate determination. 不同的命运：深入了解EPI和PE命运决定的分子机制。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-08 Print Date: 2025-03-01 DOI: 10.26508/lsa.202403091

Paraskevi Athanasouli, Tijs Vanhessche, Frederic Lluis

{"title":"Divergent destinies: insights into the molecular mechanisms underlying EPI and PE fate determination.","authors":"Paraskevi Athanasouli, Tijs Vanhessche, Frederic Lluis","doi":"10.26508/lsa.202403091","DOIUrl":"10.26508/lsa.202403091","url":null,"abstract":"Mammalian pre-implantation development is entirely devoted to the specification of extra-embryonic lineages, which are fundamental for embryo morphogenesis and support. The second fate decision is taken just before implantation, as defined by the epiblast (EPI) and the primitive endoderm (PE) specification. Later, EPI forms the embryo proper and PE contributes to the formation of the yolk sac. The formation of EPI and PE as molecularly and morphologically distinct lineages is the final step of a multistage process, which begins when bipotent progenitor cells diverge into separate fates. Despite advances in uncovering the molecular mechanisms underlying the differential transcriptional patterns that dictate how apparently identical cells make fate decisions and how lineage integrity is maintained, a detailed overview of these mechanisms is still lacking. In this review, we dissect the EPI and PE formation process into four stages (initiation, specification, segregation, and maintenance) and we provide a comprehensive understanding of the molecular mechanisms involved in lineage establishment in the mouse. In addition, we discuss the conservation of key processes in humans, based on the most recent findings.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

COA5 has an essential role in the early stage of mitochondrial complex IV assembly. COA5在线粒体复合体IV组装的早期阶段具有重要作用。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-08 Print Date: 2025-03-01 DOI: 10.26508/lsa.202403013

Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor

{"title":"COA5 has an essential role in the early stage of mitochondrial complex IV assembly.","authors":"Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor","doi":"10.26508/lsa.202403013","DOIUrl":"10.26508/lsa.202403013","url":null,"abstract":"Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

lncRNA CARINH regulates expression and function of innate immune transcription factor IRF1 in macrophages. lncRNA CARINH调控巨噬细胞中先天免疫转录因子IRF1的表达和功能。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-07 Print Date: 2025-03-01 DOI: 10.26508/lsa.202403021

Yannick Cyr, Morgane Gourvest, Grace O Ciabattoni, Tracy Zhang, Alexandra Ac Newman, Tarik Zahr, Sofie Delbare, Florencia Schlamp, Meike Dittmann, Kathryn J Moore, Coen van Solingen

{"title":"lncRNA CARINH regulates expression and function of innate immune transcription factor IRF1 in macrophages.","authors":"Yannick Cyr, Morgane Gourvest, Grace O Ciabattoni, Tracy Zhang, Alexandra Ac Newman, Tarik Zahr, Sofie Delbare, Florencia Schlamp, Meike Dittmann, Kathryn J Moore, Coen van Solingen","doi":"10.26508/lsa.202403021","DOIUrl":"10.26508/lsa.202403021","url":null,"abstract":"The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on the centrality of RNA in gene regulation and genome organization. Here, we screened for lncRNAs with putative functions in the host response to single-stranded RNA respiratory viruses. We identify CARINH as a conserved cis-acting lncRNA up-regulated in three respiratory diseases to control the expression of its antisense gene IRF1, a key transcriptional regulator of the antiviral response. CARINH and IRF1 are coordinately increased in the circulation of patients infected with human metapneumovirus, influenza A virus, or SARS-CoV-2, and in macrophages in response to viral infection or TLR3 agonist treatment. Targeted depletion of CARINH or its mouse ortholog Carinh in macrophages reduces the expression of IRF1/Irf1 and their associated target gene networks, increasing susceptibility to viral infection. Accordingly, CRISPR-mediated deletion of Carinh in mice reduces antiviral immunity, increasing viral burden upon sublethal challenge with influenza A virus. Together, these findings identify a conserved role of lncRNA CARINH in coordinating interferon-stimulated genes and antiviral immune responses.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells. 机械压缩力增加乳腺癌和胰腺癌细胞的PI3K输出信号。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-01-02 Print Date: 2025-03-01 DOI: 10.26508/lsa.202402854

Mickaël Di-Luoffo, Céline Schmitter, Emma C Barrere, Nicole Therville, Maria Chaouki, Romina D'Angelo, Silvia Arcucci, Benoit Thibault, Morgan Delarue, Julie Guillermet-Guibert

{"title":"Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells.","authors":"Mickaël Di-Luoffo, Céline Schmitter, Emma C Barrere, Nicole Therville, Maria Chaouki, Romina D'Angelo, Silvia Arcucci, Benoit Thibault, Morgan Delarue, Julie Guillermet-Guibert","doi":"10.26508/lsa.202402854","DOIUrl":"10.26508/lsa.202402854","url":null,"abstract":"Mechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth and the environment remodeling explain their high intensity of compressive forces. However, the sensitivity of compressed cells to targeted therapies remains poorly known. In breast and pancreatic cancer cells, pharmacological PI3K inactivation decreased cell number and induced apoptosis. These effects were accentuated when we applied 2D compression forces in mechanically responsive cells. Compression selectively induced the overexpression of PI3K isoforms and PI3K/AKT pathway activation. Furthermore, transcriptional effects of PI3K inhibition and compression converged to control the expression of an autophagy regulator, GABARAP, whose level was inversely associated with PI3K inhibitor sensitivity under compression. Compression alone blocked autophagy flux in all tested cells, whereas inactivation of basal PI3K activity restored autophagy flux only in mechanically non-responsive compressed cells. This study provides direct evidence for the role of the PI3K/AKT pathway in compression-induced mechanotransduction. PI3K inhibition promotes apoptosis or autophagy, explaining PI3K importance to control cancer cell survival under compression.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Molecular analysis of acute pyelonephritis-excessive innate and attenuated adaptive immunity.

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-12-20 Print Date: 2025-03-01 DOI: 10.26508/lsa.202402926

Ines Ambite, Sing Ming Chao, Therese Rosenblad, Richard Hopkins, Petter Storm, Yong Hong Ng, Indra Ganesan, Magnus Lindén, Farhan Haq, Thi Hien Tran, Shahram Ahmadi, Bernett Lee, Swaine L Chen, Gabriela Godaly, Per Brandström, John E Connolly, Catharina Svanborg

{"title":"Molecular analysis of acute pyelonephritis-excessive innate and attenuated adaptive immunity.","authors":"Ines Ambite, Sing Ming Chao, Therese Rosenblad, Richard Hopkins, Petter Storm, Yong Hong Ng, Indra Ganesan, Magnus Lindén, Farhan Haq, Thi Hien Tran, Shahram Ahmadi, Bernett Lee, Swaine L Chen, Gabriela Godaly, Per Brandström, John E Connolly, Catharina Svanborg","doi":"10.26508/lsa.202402926","DOIUrl":"10.26508/lsa.202402926","url":null,"abstract":"This study investigated the molecular basis of disease severity in acute pyelonephritis (APN), a common and potentially life-threatening bacterial infection. Two cohorts of infants with febrile urinary tract infection were included. Renal involvement was defined by DMSA scans and molecular disease determinants by gene expression analysis and proteomic screens, at diagnosis and after 6 mo. Innate immune hyper-activation, systemically and locally in the urinary tract, was defined as a cytokine storm. Neutrophil degranulation and renal toxicity genes were strongly regulated, with overexpression in the APN group (first DMSA+). Adaptive immune attenuation in the APN group further supported the notion of an immune imbalance. DNA exome genotyping identified APN and febrile urinary tract infection as genetically distinct and scarring associated genes, but the activation of renal toxicity genes during acute infection was unrelated to the development of renal scarring. The results define APN as a hyper-inflammatory disorder with the characteristics of a cytokine storm combined with adaptive immune attenuation. The findings are consistent with innate immune dysfunctions and neutrophil disorders identified as determinants of APN susceptibility in genetic models.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD. RuvBL1/2在多种C9orf72-ALS/FTD模型中减少毒性二肽重复蛋白负荷。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-12-05 Print Date: 2025-02-01 DOI: 10.26508/lsa.202402757

Christopher P Webster, Bradley Hall, Olivia M Crossley, Dana Dauletalina, Marianne King, Ya-Hui Lin, Lydia M Castelli, Zih-Liang Yang, Ian Coldicott, Ergita Kyrgiou-Balli, Adrian Higginbottom, Laura Ferraiuolo, Kurt J De Vos, Guillaume M Hautbergue, Pamela J Shaw, Ryan Jh West, Mimoun Azzouz

{"title":"RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.","authors":"Christopher P Webster, Bradley Hall, Olivia M Crossley, Dana Dauletalina, Marianne King, Ya-Hui Lin, Lydia M Castelli, Zih-Liang Yang, Ian Coldicott, Ergita Kyrgiou-Balli, Adrian Higginbottom, Laura Ferraiuolo, Kurt J De Vos, Guillaume M Hautbergue, Pamela J Shaw, Ryan Jh West, Mimoun Azzouz","doi":"10.26508/lsa.202402757","DOIUrl":"10.26508/lsa.202402757","url":null,"abstract":"A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

4G cloning: rapid gene assembly for expression of multisubunit protein complexes in diverse hosts. 4G克隆：在不同宿主中表达多亚单位蛋白复合物的快速基因组装。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-12-02 Print Date: 2025-01-01 DOI: 10.26508/lsa.202402899

Michael Taschner, Joe Bradley Dickinson, Florian Roisné-Hamelin, Stephan Gruber

引用次数: 0