METABOTROPIC GLUTAMATE RECEPTORS IN NEURODEGENERATION

Summary

Principal Investigator: Anne Young
Abstract: Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animal models now exist, the exact mechanisms by which mutant genes cause neurologic diseases remains unclear. Unless the etiologic mechanisms underlying neurodegenerative diseases are clearly identified,rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemstry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases. PERFORMANCE blTE(S) (organization, city, state) Neurology Service Massachusetts General Hospital Fruit Street Boston, MA 02114 KEY PERSONNEL. See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below. Name Organization Role on Project Anne B. Young, M.D.,Ph.D. Massachusetts General Hospital Principal Investigator L)J Jang-Ho Cha, M.D., Ph.D. Massachusetts General Hospital Investigator QJ David G. Standaert, M.D., Ph.D. Massachusetts General Hospital Investigator C l^Anthone Dunah, Ph.D. Massachusetts General Hospital Investigator ^-l/Zane R. Hollingsworth, M.P.H. Massachusetts General Hospital Investigator Lv LiannaR. Orlando, M.M.Sc.i^ ^ Massachusetts General Hospital Investigator Laurie Farrell,B.S. Massachusetts General Hospital Research Assistant Tara Razzano,B.S. Massachusetts General Hospital Research Assistant PHS 398 (Rev. 4/98) Page 2 BB Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. Young, Anne B. CC Principal^^tigator/Program Director (Last, first, middle):. Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
Funding Period: 1995-08-15 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1
    Birgit Zucker
    Department of Neurology, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA
    Hum Mol Genet 14:179-89. 2005
  2. pmc Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease
    C L Benn
    MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129 4404, USA
    Neuroscience 147:354-72. 2007
  3. ncbi Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5
    Lianna R Orlando
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, 02129, USA
    J Neurochem 110:557-69. 2009
  4. ncbi Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease
    Caroline L Benn
    Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA
    J Neuropathol Exp Neurol 69:817-27. 2010
  5. ncbi Metabotropic glutamate receptor 1 (mGluR1): antibody specificity and receptor expression in cultured primary neurons
    Ramses Ayala
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street B114 2000, Boston, MA 02129, United States
    J Neurosci Methods 204:221-6. 2012

Scientific Experts

  • Birgit Zucker
  • Jang Ho Cha
  • Ramses Ayala
  • Lianna R Orlando
  • Lauren R Kett
  • Anthone W Dunah
  • Anne B Young
  • Caroline L Benn
  • C L Benn
  • Tiffany L Leach
  • Ruth Luthi-Carter
  • Kwabena L Blankson
  • Tara L Spires
  • Darlene R Goldstein
  • Anthony J Hannan
  • Ghazaleh Sadri-Vakili
  • Anton van Dellen
  • James M Olson
  • Alexandre Kuhn
  • Joel Pritchard
  • Sudeb C Dalai
  • Jay Duffner
  • Li Huei Tsai
  • Allison A Curley
  • D Cristopher Bragg
  • Y Deng
  • R Graham
  • L A Farrell
  • E J Slow
  • M R Hayden

Detail Information

Publications6

  1. ncbi Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1
    Birgit Zucker
    Department of Neurology, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA
    Hum Mol Genet 14:179-89. 2005
    ....
  2. pmc Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease
    C L Benn
    MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129 4404, USA
    Neuroscience 147:354-72. 2007
    ..The decrease in preproenkephalin mRNA suggests a selective transcriptional deficit, as opposed to neuronal loss, and could additionally contribute to the abnormal motor symptoms in YAC128 mice...
  3. ncbi Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5
    Lianna R Orlando
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, 02129, USA
    J Neurochem 110:557-69. 2009
    ..Phosphorylation of the mGluR homer-binding domain, in contrast to homer 1a induction, provides a novel mechanism for potentially regulating a subset of homer interactions...
  4. ncbi Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease
    Caroline L Benn
    Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA
    J Neuropathol Exp Neurol 69:817-27. 2010
    ..Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression...
  5. ncbi Metabotropic glutamate receptor 1 (mGluR1): antibody specificity and receptor expression in cultured primary neurons
    Ramses Ayala
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street B114 2000, Boston, MA 02129, United States
    J Neurosci Methods 204:221-6. 2012
    ..Together, these data provide a baseline characterization of antibodies that can and cannot be reliably used in these types of studies, and will hopefully facilitate and positively impact the research efforts of others studying mGluR1...