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EMBO Molecular Medicine

Gabriele Civiletto, Sukru Anil Dogan, Raffaele Cerutti, Gigliola Fagiolari, Maurizio Moggio, Costanza Lamperti, Cristiane Benincá, Carlo Viscomi, Massimo Zeviani
The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific Cox15 knockout mouse ( Cox15 sm / sm ). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15 sm / sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15 sm / sm mice...
October 11, 2018: EMBO Molecular Medicine
Snehajyoti Chatterjee, Raphaelle Cassel, Anne Schneider-Anthony, Karine Merienne, Brigitte Cosquer, Laura Tzeplaeff, Sarmistha Halder Sinha, Manoj Kumar, Piyush Chaturbedy, Muthusamy Eswaramoorthy, Stéphanie Le Gras, Céline Keime, Olivier Bousiges, Patrick Dutar, Petnoi Petsophonsakul, Claire Rampon, Jean-Christophe Cassel, Luc Buée, David Blum, Tapas K Kundu, Anne-Laurence Boutillier
Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers...
October 1, 2018: EMBO Molecular Medicine
Mayur Dembla, Ajay Kesharwani, Sivaraman Natarajan, Claudia Fecher-Trost, Richard Fairless, Sarah K Williams, Veit Flockerzi, Ricarda Diem, Karin Schwarz, Frank Schmitz
Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto-immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well-validated mouse models of optic neuritis that ribbon synapses in the myelin-free retina are targeted by an auto-reactive immune system even before alterations in the optic nerve have developed. The auto-immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses...
September 28, 2018: EMBO Molecular Medicine
Joy Chakraborty, Sophia von Stockum, Elena Marchesan, Federico Caicci, Vanni Ferrari, Aleksandar Rakovic, Christine Klein, Angelo Antonini, Luigi Bubacco, Elena Ziviani
Mitochondrial autophagy or mitophagy is a key process that allows selective sequestration and degradation of dysfunctional mitochondria to prevent excessive reactive oxygen species, and activation of cell death. Recent studies revealed that ubiquitin-proteasome complex activity and mitochondrial membrane rupture are key steps preceding mitophagy, in combination with the ubiquitination of specific outer mitochondrial membrane (OMM) proteins. The deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy...
September 24, 2018: EMBO Molecular Medicine
Isha Akhtar-Schäfer, Luping Wang, Tim U Krohne, Heping Xu, Thomas Langmann
This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age-related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss...
September 17, 2018: EMBO Molecular Medicine
Ulf Neumann, Mike Ufer, Laura H Jacobson, Marie-Laure Rouzade-Dominguez, Gunilla Huledal, Carine Kolly, Rainer M Lüönd, Rainer Machauer, Siem J Veenstra, Konstanze Hurth, Heinrich Rueeger, Marina Tintelnot-Blomley, Matthias Staufenbiel, Derya R Shimshek, Ludovic Perrot, Wilfried Frieauff, Valerie Dubost, Hilmar Schiller, Barbara Vogg, Karen Beltz, Alexandre Avrameas, Sandrine Kretz, Nicole Pezous, Jean-Michel Rondeau, Nicolau Beckmann, Andreas Hartmann, Stefan Vormfelde, Olivier J David, Bruno Galli, Rita Ramos, Ana Graf, Cristina Lopez Lopez
The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP-transgenic mice...
September 17, 2018: EMBO Molecular Medicine
Paul Hiebert, Sabine Werner
No abstract text is available yet for this article.
September 17, 2018: EMBO Molecular Medicine
Anett Pfeiffer, Frederic B Thalheimer, Sylvia Hartmann, Annika M Frank, Ruben R Bender, Simon Danisch, Caroline Costa, Winfried S Wels, Ute Modlich, Renata Stripecke, Els Verhoeyen, Christian J Buchholz
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells...
September 17, 2018: EMBO Molecular Medicine
Kyle Thompson, Nicole Mai, Monika Oláhová, Filippo Scialó, Luke E Formosa, David A Stroud, Madeleine Garrett, Nichola Z Lax, Fiona M Robertson, Cristina Jou, Andres Nascimento, Carlos Ortez, Cecilia Jimenez-Mallebrera, Steven A Hardy, Langping He, Garry K Brown, Paula Marttinen, Robert McFarland, Alberto Sanz, Brendan J Battersby, Penelope E Bonnen, Michael T Ryan, Zofia Ma Chrzanowska-Lightowlers, Robert N Lightowlers, Robert W Taylor
OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c...
September 10, 2018: EMBO Molecular Medicine
Aurelio Reyes, Laura Melchionda, Alberto Burlina, Alan J Robinson, Daniele Ghezzi, Massimo Zeviani
TIMM50 is an essential component of the TIM23 complex, the mitochondrial inner membrane machinery that imports cytosolic proteins containing a mitochondrial targeting presequence into the mitochondrial inner compartment. Whole exome sequencing (WES) identified compound heterozygous pathogenic mutations in TIMM50 in an infant patient with rapidly progressive, severe encephalopathy. Patient fibroblasts presented low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential, and impaired TIM23-dependent protein import...
September 6, 2018: EMBO Molecular Medicine
María Virtudes Céspedes, Ugutz Unzueta, Anna Aviñó, Alberto Gallardo, Patricia Álamo, Rita Sala, Alejandro Sánchez-Chardi, Isolda Casanova, María Antònia Mangues, Antonio Lopez-Pousa, Ramón Eritja, Antonio Villaverde, Esther Vázquez, Ramón Mangues
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis-initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22-GFP-H6-FdU) that selectively delivers Floxuridine to CXCR4+ cells. In contrast to free oligo-FdU, intravenous T22-GFP-H6-FdU selectively accumulates and internalizes in CXCR4+ cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re-initiation capacity...
September 6, 2018: EMBO Molecular Medicine
Jacob Insua-Rodríguez, Maren Pein, Tsunaki Hongu, Jasmin Meier, Arnaud Descot, Camille M Lowy, Etienne De Braekeleer, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Thordur Oskarsson
Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer...
September 6, 2018: EMBO Molecular Medicine
Cécile Otten, Jessica Knox, Gwénola Boulday, Mathias Eymery, Marta Haniszewski, Martin Neuenschwander, Silke Radetzki, Ingo Vogt, Kristina Hähn, Coralie De Luca, Cécile Cardoso, Sabri Hamad, Carla Igual Gil, Peter Roy, Corinne Albiges-Rizo, Eva Faurobert, Jens P von Kries, Mónica Campillos, Elisabeth Tournier-Lasserve, W Brent Derry, Salim Abdelilah-Seyfried
Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells...
September 4, 2018: EMBO Molecular Medicine
Maiko de Kerckhove, Katsuya Tanaka, Takahiro Umehara, Momoko Okamoto, Sotaro Kanematsu, Hiroko Hayashi, Hiroki Yano, Soushi Nishiura, Shiho Tooyama, Yutaka Matsubayashi, Toshimitsu Komatsu, Seongjoon Park, Yuka Okada, Rina Takahashi, Yayoi Kawano, Takehisa Hanawa, Keisuke Iwasaki, Tadashige Nozaki, Hidetaka Torigoe, Kazuya Ikematsu, Yutaka Suzuki, Katsumi Tanaka, Paul Martin, Isao Shimokawa, Ryoichi Mori
Argonaute 2 bound mature microRNA (Ago2-miRNA) complexes are key regulators of the wound inflammatory response and function in the translational processing of target mRNAs. In this study, we identified four wound inflammation-related Ago2-miRNAs ( miR-139-5p , miR-142-3p , miR-142-5p , and miR-223 ) and show that miR-223 is critical for infection control. miR-223 Y /- mice exhibited delayed sterile healing with prolonged neutrophil activation and interleukin-6 expression, and markedly improved repair of Staphylococcus aureus -infected wounds...
August 31, 2018: EMBO Molecular Medicine
Xiao Sun, Jing Hui Guo, Dan Zhang, Jun-Jiang Chen, Wei Yin Lin, Yun Huang, Hui Chen, Wen Qing Huang, Yifeng Liu, Lai Ling Tsang, Mei Kuen Yu, Yiu Wa Chung, Xiaohua Jiang, Hefeng Huang, Hsiao Chang Chan, Ye Chun Ruan
The shift of cytokine profile from anti- to pro-inflammatory is the most recognizable sign of labor, although the underlying mechanism remains elusive. Here, we report that the epithelial sodium channel (ENaC) is upregulated and activated in the uterus at labor in mice. Mechanical activation of ENaC results in phosphorylation of CREB and upregulation of pro-inflammatory cytokines as well as COX-2/PGE2 in uterine epithelial cells. ENaC expression is also upregulated in mice with RU486-induced preterm labor as well as in women with preterm labor...
August 28, 2018: EMBO Molecular Medicine
Alexander Greenhough, Clare Bagley, Kate J Heesom, David B Gurevich, David Gay, Mark Bond, Tracey J Collard, Chris Paraskeva, Paul Martin, Owen J Sansom, Karim Malik, Ann C Williams
Hypoxia is a hallmark of solid tumours and a key physiological feature distinguishing cancer from normal tissue. However, a major challenge remains in identifying tractable molecular targets that hypoxic cancer cells depend on for survival. Here, we used SILAC-based proteomics to identify the orphan G protein-coupled receptor GPRC5A as a novel hypoxia-induced protein that functions to protect cancer cells from apoptosis during oxygen deprivation. Using genetic approaches in vitro and in vivo , we reveal HIFs as direct activators of GPRC5A transcription...
August 24, 2018: EMBO Molecular Medicine
Gloria M Palomo, Veronica Granatiero, Hibiki Kawamata, Csaba Konrad, Michelle Kim, Andrea J Arreguin, Dazhi Zhao, Teresa A Milner, Giovanni Manfredi
Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1-G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted...
August 20, 2018: EMBO Molecular Medicine
Yang Chen, Valerie S LeBleu, Julienne L Carstens, Hikaru Sugimoto, Xiaofeng Zheng, Shruti Malasi, Dieter Saur, Raghu Kalluri
Epithelial-to-mesenchymal transition (EMT) is a recognized eukaryotic cell differentiation program that is also observed in association with invasive tumors. Partial EMT program in carcinomas imparts cancer cells with mesenchymal-like features and is proposed as essential for metastasis. Precise determination of the frequency of partial EMT program in cancer cells in tumors and its functional role in metastases needs unraveling. Here, we employed mesenchymal cell reporter mice driven by αSMA-Cre and Fsp1-Cre with genetically engineered mice that develop spontaneous pancreatic ductal adenocarcinoma (PDAC) to monitor partial EMT program...
August 17, 2018: EMBO Molecular Medicine
Johanna Kondelin, Kari Salokas, Lilli Saarinen, Kristian Ovaska, Heli Rauanheimo, Roosa-Maria Plaketti, Jiri Hamberg, Xiaonan Liu, Leena Yadav, Alexandra E Gylfe, Tatiana Cajuso, Ulrika A Hänninen, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Tomas Tanskanen, Mervi Aavikko, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Anna Lepistö, Selja Koskensalo, Jan Böhm, Jukka-Pekka Mecklin, Halit Ongen, Emmanouil T Dermitzakis, Outi Kilpivaara, Pia Vahteristo, Mikko Turunen, Sampsa Hautaniemi, Sari Tuupanen, Auli Karhu, Niko Välimäki, Markku Varjosalo, Esa Pitkänen, Lauri A Aaltonen
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized...
September 2018: EMBO Molecular Medicine
Murugan Kalimutho, Debottam Sinha, Jessie Jeffery, Katia Nones, Sriganesh Srihari, Winnie C Fernando, Pascal Hg Duijf, Claire Vennin, Prahlad Raninga, Devathri Nanayakkara, Deepak Mittal, Jodi M Saunus, Sunil R Lakhani, J Alejandro López, Kevin J Spring, Paul Timpson, Brian Gabrielli, Nicola Waddell, Kum Kum Khanna
The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis...
September 2018: EMBO Molecular Medicine
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