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  • Research Article
    Therapeutic potential of targeting microRNA‐10b in established intracranial glioblastoma: first steps toward the clinic
    Therapeutic potential of targeting microRNA‐10b in established intracranial glioblastoma: first steps toward the clinic
    1. Nadiya M Teplyuk1,
    2. Erik J Uhlmann1,
    3. Galina Gabriely1,
    4. Natalia Volfovsky2,
    5. Yang Wang1,
    6. Jian Teng3,
    7. Priya Karmali4,
    8. Eric Marcusson4,
    9. Merlene Peter1,
    10. Athul Mohan1,
    11. Yevgenya Kraytsberg1,
    12. Ron Cialic1,
    13. E Antonio Chiocca5,
    14. Jakub Godlewski5,
    15. Bakhos Tannous3 and
    16. Anna M Krichevsky*,1
    1. 1Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA
    2. 2Simons Foundation, New York, NY, USA
    3. 3Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
    4. 4Regulus Therapeutics Inc., San Diego, CA, USA
    5. 5Department of Neurosurgery, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA
    1. *Corresponding author. Tel: +1 617 525 5195; E‐mail: akrichevsky{at}rics.bwh.harvard.edu

    Oncogenic miR‐10b highly expressed in glioblastoma and absent in normal brain tissues promotes the growth of heterogeneous glioma cell types. Teplyuk et al. describe common genes regulated by miR‐10b in glioma stem cells and demonstrate the efficacy of miR‐10b inhibition in established GBM models.

    Synopsis

    Oncogenic miR‐10b highly expressed in glioblastoma and absent in normal brain tissues promotes the growth of heterogeneous glioma cell types. Teplyuk et al. describe common genes regulated by miR‐10b in glioma stem cells and demonstrate the efficacy of miR‐10b inhibition in established GBM models.

    • mRNA splicing and processing factors are regulated by miR‐10b through the non‐canonical 5′UTR binding in glioma‐derived neurospheres.

    • Growth of orthotopic glioblastoma (GBM) xenografts and allografts in mouse models is attenuated by local and systemic delivery of miR+NA inhibitors.

    • No systemic toxicity of miR‐10b inhibitors’ administration by local or systemic routes was observed.

    • alternative splicing
    • brain tumor
    • microRNA
    • oligonucleotide therapeutics
    • stem cells
    • Received June 1, 2015.
    • Revision received December 22, 2015.
    • Accepted January 11, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Nadiya M Teplyuk, Erik J Uhlmann, Galina Gabriely, Natalia Volfovsky, Yang Wang, Jian Teng, Priya Karmali, Eric Marcusson, Merlene Peter, Athul Mohan, Yevgenya Kraytsberg, Ron Cialic, E Antonio Chiocca, Jakub Godlewski, Bakhos Tannous, Anna M Krichevsky
  • Research Article
    Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing
    Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing
    1. Annalisa Buniello*,1,2,
    2. Neil J Ingham1,2,
    3. Morag A Lewis1,2,
    4. Andreea C Huma2,
    5. Raquel Martinez‐Vega2,3,4,
    6. Isabel Varela‐Nieto3,4,
    7. Gema Vizcay‐Barrena5,
    8. Roland A Fleck5,
    9. Oliver Houston6,
    10. Tanaya Bardhan6,
    11. Stuart L Johnson6,
    12. Jacqueline K White2,
    13. Huijun Yuan7,
    14. Walter Marcotti6 and
    15. Karen P Steel*,1,2
    1. 1Wolfson Centre For Age‐Related Diseases, King's College London, London, UK
    2. 2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
    3. 3Instituto de Investigaciones Biomédicas Alberto Sols, CSIC‐UAM, Madrid, Spain
    4. 4Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 761, Instituto de Salud Carlos III, Madrid, Spain
    5. 5Centre for Ultrastructural Imaging, King's College London, London, UK
    6. 6Department of Biomedical Science, University of Sheffield, Sheffield, UK
    7. 7Medical Genetics Center, Southwest Hospital Third Military Medical University, Chongqing, China
    1. * Corresponding author. Tel: +44 207 848 6803; E‐mail: annalisa.buniello{at}kcl.ac.uk
      Corresponding author. Tel: +44 207 848 6203; E‐mail: karen.steel{at}kcl.ac.uk

    WBP2 was found to underlie deafness in mouse and patients. Wbp2‐deficient mice were used as a genetic tool to gain insight into the functional link between hormonal signalling and hearing impairment.

    Synopsis

    WBP2 was found to underlie deafness in mouse and patients. Wbp2‐deficient mice were used as a genetic tool to gain insight into the functional link between hormonal signalling and hearing impairment.

    • WBP2 mutations lead to deafness in mouse and humans.

    • In the Wbp2‐mutant mouse, the earliest abnormality is swelling of afferent nerve endings below inner hair cells and mice show progressive high‐frequency hearing loss.

    • Wbp2 deficiency leads to reduced expression of estrogen and progesterone receptors in the cochlea and disrupted expression of key post‐synaptic proteins.

    • glutamate excitotoxicity
    • hearing impairment
    • hormonal signalling
    • ribbon synapses
    • transcriptional coactivator
    • Received June 9, 2015.
    • Revision received December 18, 2015.
    • Accepted December 21, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Annalisa Buniello, Neil J Ingham, Morag A Lewis, Andreea C Huma, Raquel Martinez‐Vega, Isabel Varela‐Nieto, Gema Vizcay‐Barrena, Roland A Fleck, Oliver Houston, Tanaya Bardhan, Stuart L Johnson, Jacqueline K White, Huijun Yuan, Walter Marcotti, Karen P Steel
  • Research Article
    OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination
    OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination
    1. Maria Francesca Baietti1,2,,
    2. Michal Simicek1,26,
    3. Layka Abbasi Asbagh1,2,
    4. Enrico Radaelli1,2,
    5. Sam Lievens3,4,
    6. Jonathan Crowther1,2,
    7. Mikhail Steklov1,2,
    8. Vasily N Aushev1,2,5,
    9. David Martínez García1,2,
    10. Jan Tavernier3,4 and
    11. Anna A Sablina*,1,2
    1. 1Center for the Biology of Disease, VIB, Leuven, Belgium
    2. 2Center for Human Genetics, KU Leuven, Leuven, Belgium
    3. 3Department of Medical Protein Research, VIB, Leuven, Belgium
    4. 4Department of Biochemistry, Gent University, Gent, Belgium
    5. 5Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Moscow, Russia
    6. 6PNAC, MRC, LMB, Cambridge, UK
    1. *Corresponding author. Tel: +32 16330790; Fax: +32 16330145; E‐mail: anna.sablina{at}cme.vib-kuleuven.be
    1. These authors equally contributed to this work

    The regulation of RAS mono‐ubiquitination by OTUB1 is an alternative mechanism of RAS activation during lung cancer development.

    Synopsis

    The regulation of RAS mono‐ubiquitination by OTUB1 is an alternative mechanism of RAS activation during lung cancer development.

    • OTUB1 negatively regulates RAS mono‐ubiquitination resulting in sequestration of RAS on the plasma membrane.

    • OTUB1 promotes RAS signaling and tumorigenic growth of wild‐type KRAS lung adenocarcinoma cells.

    • OTUB1 up‐regulation is associated with poorer survival of wild‐type KRAS lung adenocarcinoma patients.

    • lung cancer
    • RAS
    • reversible ubiquitination
    • Received October 23, 2015.
    • Revision received January 5, 2016.
    • Accepted January 11, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Maria Francesca Baietti, Michal Simicek, Layka Abbasi Asbagh, Enrico Radaelli, Sam Lievens, Jonathan Crowther, Mikhail Steklov, Vasily N Aushev, David Martínez García, Jan Tavernier, Anna A Sablina
  • News & Views
    Amyloid‐β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing
    Amyloid‐β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing
    1. Veronika Boczonadi1 and
    2. Rita Horvath (rita.horvath{at}ncl.ac.uk)1
    1. 1Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK

    There is increasing evidence that common molecular pathways in neurons are closely linked with mitochondrial function and that mitochondrial dysfunction is connected to various forms of neurodegenerative diseases. For instance, mitochondria are involved in amyloid‐β (Aβ) deposition in Alzheimer's disease, although the exact molecular pathways remain largely unknown. Brunetti et al (2015) in this issue of EMBO Molecular Medicine provide a novel link between Aβ accumulation and mitochondria. A pathogenic mutation in a Norwegian family in the mitochondrial metallopeptidase PITRM1 is found to underlie a novel mitochondrial neurodegenerative phenotype associated with Aβ accumulation.

    See also: D Brunetti et al

    Boczonadi and Horvath comment on the Brunetti et al's paper in this issue describing a mitochondrial metallopeptidase PITRM1 pathogenic mutation in a Norwegian family, underlying a novel mitochondrial neurodegenerative phenotype with Aβ accumulation.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Veronika Boczonadi, Rita Horvath
  • Research Article
    mTORC2 sustains thermogenesis via Akt‐induced glucose uptake and glycolysis in brown adipose tissue
    mTORC2 sustains thermogenesis via Akt‐induced glucose uptake and glycolysis in brown adipose tissue
    1. Verena Albert1,
    2. Kristoffer Svensson1,
    3. Mitsugu Shimobayashi1,
    4. Marco Colombi1,
    5. Sergio Muñoz2,3,
    6. Veronica Jimenez2,3,
    7. Christoph Handschin1,
    8. Fatima Bosch2,3 and
    9. Michael N Hall*,1
    1. 1Biozentrum, University of Basel, Basel, Switzerland
    2. 2Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
    3. 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
    1. *Corresponding author. Tel: +41 61 267 21 50; E‐mail: m.hall{at}unibas.ch

    Albert et al show that β‐adrenergic stimulation activates mTORC2 in brown adipocytes. Active mTORC2 signaling in BAT is required for cold‐induced stimulation of glucose uptake and glycolysis to maintain temperature homeostasis upon cold stress.

    Synopsis

    Albert et al show that β‐adrenergic stimulation activates mTORC2 in brown adipocytes. Active mTORC2 signaling in BAT is required for cold‐induced stimulation of glucose uptake and glycolysis to maintain temperature homeostasis upon cold stress.

    • β‐adrenergic stimulation activates mTORC2 in brown adipocytes.

    • Mice deficient for mTORC2 in adipose tissue are hypothermic and sensitive to cold.

    • mTORC2 in BAT stimulates cold‐induced glucose uptake and glycolysis via Akt.

    • Restoration of glucose uptake in BAT of AdRiKO mice restores temperature homeostasis.

    • brown adipose tissue
    • glucose uptake
    • mTORC2
    • thermogenesis
    • Received July 9, 2015.
    • Revision received December 10, 2015.
    • Accepted December 14, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Verena Albert, Kristoffer Svensson, Mitsugu Shimobayashi, Marco Colombi, Sergio Muñoz, Veronica Jimenez, Christoph Handschin, Fatima Bosch, Michael N Hall
  • Research Article
    Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
    Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
    1. Dario Brunetti1,,
    2. Janniche Torsvik2,,
    3. Cristina Dallabona3,
    4. Pedro Teixeira4,
    5. Pawel Sztromwasser5,6,
    6. Erika Fernandez‐Vizarra1,
    7. Raffaele Cerutti1,
    8. Aurelio Reyes1,
    9. Carmela Preziuso7,
    10. Giulia D'Amati7,
    11. Enrico Baruffini3,
    12. Paola Goffrini3,
    13. Carlo Viscomi1,
    14. Ileana Ferrero3,
    15. Helge Boman8,
    16. Wenche Telstad9,
    17. Stefan Johansson5,8,
    18. Elzbieta Glaser4,
    19. Per M Knappskog5,8,
    20. Massimo Zeviani*,1 and
    21. Laurence A Bindoff*,2,10
    1. 1MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK
    2. 2Department of Neurology, Haukeland University Hospital, Bergen, Norway
    3. 3Department of Life Sciences, University of Parma, Parma, Italy
    4. 4Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
    5. 5Department of Clinical Science, University of Bergen, Bergen, Norway
    6. 6Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
    7. 7Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome, Rome, Italy
    8. 8Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    9. 9Department of Neurology, Førde Hospital, Førde, Norway
    10. 10Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
    1. * Corresponding author. Tel: +44 1223 252704; Fax: +44 1223 252715; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk
      Corresponding author. Tel: +47 55975096; Fax: +47 55975164; E‐mail: laurence.bindoff{at}nevro.uib.no
    1. These authors contributed equally to this work

    A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals.

    Synopsis

    A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals.

    • A homozygous disease segregating missense mutation was found in the PITRM1 gene in two siblings of a consanguineous family.

    • The pathogenic role of the mutation, causing PITRM1 instability, was validated by in vitro assay, characterization of mutant fibroblasts from patients and in PITRM1 knocked‐down human fibroblasts, and in a mutant yeast model.

    • A hemizygous PITRM1 knockout mouse displayed reduced amount of PITRM1, associated with slowly progressive neurodegeneration, hallmarked by accumulation of Aβ amyloid in the brain.

    • amyloid beta
    • mitochondrial targeting sequence
    • mitochondrial disease
    • neurodegeneration
    • pitrilysin 1
    • Received September 26, 2015.
    • Revision received November 19, 2015.
    • Accepted November 23, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Dario Brunetti, Janniche Torsvik, Cristina Dallabona, Pedro Teixeira, Pawel Sztromwasser, Erika Fernandez‐Vizarra, Raffaele Cerutti, Aurelio Reyes, Carmela Preziuso, Giulia D'Amati, Enrico Baruffini, Paola Goffrini, Carlo Viscomi, Ileana Ferrero, Helge Boman, Wenche Telstad, Stefan Johansson, Elzbieta Glaser, Per M Knappskog, Massimo Zeviani, Laurence A Bindoff