Neurodegeneration in Aging Retarded Mice

Summary

Principal Investigator: Roger Albin
Abstract: DESCRIPTION (provided by applicant): Neurodegenerative disorders, both sporadic and inherited, are associated commonly with aging. The wide variety of likely mechanisms of action in different neurodegenerative disorders suggests that common features of normal aging underlie the increased predisposition to suffer from neurodegenerative disorders. The age dependence of neurodegeneration is unexplained and is a fundamental problem in understanding these common pathologies. Understanding the interaction of aging with neurodegeneration requires the development of model systems in which the rates of aging and neurodegeneration can be varied systematically. The development of murine genetic models of polyglutamine (polyQ) diseases with varying phenotypes and the existence of mouse lines with retarded aging offers the opportunity to develop models in which the interaction of aging and neurodegeneration can be studied systematically. We propose to develop compound mice lines carrying alleles that cause polyQ disease phenotypes and alleles that retard normal aging to study the impact of altering aging on the polyQ disease-like phenotypes. We focus on a phylogenetically conserved signaling pathway that influences aging in several invertebrate and vertebrate species;the Growth Hormone-insulin/IGF - Aki - FOXO pathway. Our hypothesis is that retarding aging by disrupting the Growth Hormone - insulin/IGF - Akt - FOXO pathway will delay mortality, and retard the development of behavioral and pathologic abnormalities secondary to induced polyQ mutations. This hypothesis is supported by impressive work in invertebrates but has not been tested in mammals. Our specific aims are: 1) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation at the Pit1 (Snell dwarf) locus. 2) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation mutation at the Growth Hormone receptor (GHR) locus. 3) To characterize the lifespan, and behavioral and pathologic features of these compound mutants. Our long term goal is to understand the interaction of aging and neurodegeneration. If these experiments are successful, we will have models in hand to study the aging-neurodegeneration relationship. These models would be useful in dissecting the specific mechanisms underlying the aging-neurodegeneration relationship. We would be able to vary the rate of neurodegeneration by developing additional compound models with more slowly progressive polyQ disease alleles. We would be able to extend these approaches also to other neurodegenerations such as Alzheimer disease and Motor Neuron disease. PUBLIC HEALTH RELEVANCE The onset of most degenerative brain diseases, like Alzheimer disease and Parkinson disease, occurs later in life. Some unknown features of aging make the human brain susceptible to these degenerative disorders. We propose to develop new mouse models that will allow analysis of the interaction of normal aging and neurodegeneration.
Funding Period: 2008-09-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc History of falls in Parkinson disease is associated with reduced cholinergic activity
    N I Bohnen
    Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor 48105 9755, USA
    Neurology 73:1670-6. 2009
  2. pmc Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington's disease
    Giselle M Perry
    Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Hum Mol Genet 19:3354-71. 2010
  3. pmc Early autophagic response in a novel knock-in model of Huntington disease
    Mary Y Heng
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 2200, USA
    Hum Mol Genet 19:3702-20. 2010
  4. pmc Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease
    Sara J Tallaksen-Greene
    Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, MI 48105, USA
    Exp Neurol 225:402-7. 2010
  5. pmc Early alterations of autophagy in Huntington disease-like mice
    Mary Y Heng
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Autophagy 6:1206-8. 2010

Scientific Experts

  • NICOLAAS IDA BOHNEN
  • Mary Y Heng
  • Roger L Albin
  • Peter J Detloff
  • Sara J Tallaksen-Greene
  • Giselle M Perry
  • Henry L Paulson
  • Kasha Benton
  • Mathieu Lesort
  • Sara Tallaksen-Greene
  • Anita Janiszewska
  • Ashish Kumar
  • Alex Osmand
  • Andrew Kneynsberg
  • Thomas van Groen
  • Jesse M Hunter
  • Lech Ruprecht
  • MATHIEU J LESORT
  • Duy K Duong

Detail Information

Publications5

  1. pmc History of falls in Parkinson disease is associated with reduced cholinergic activity
    N I Bohnen
    Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor 48105 9755, USA
    Neurology 73:1670-6. 2009
    ..To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD)...
  2. pmc Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington's disease
    Giselle M Perry
    Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Hum Mol Genet 19:3354-71. 2010
    ..The results of this study demonstrate that increasing neuronal mitochondrial Ca2+-buffering capacity is not beneficial in the R6/2 mouse model of HD...
  3. pmc Early autophagic response in a novel knock-in model of Huntington disease
    Mary Y Heng
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 2200, USA
    Hum Mol Genet 19:3702-20. 2010
    ..Early and sustained expression of autophagy-related proteins in this genetically precise mouse model of HD suggests that the alteration of autophagic flux is an important and early component of the neuronal response to mhtt...
  4. pmc Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease
    Sara J Tallaksen-Greene
    Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, MI 48105, USA
    Exp Neurol 225:402-7. 2010
    ....
  5. pmc Early alterations of autophagy in Huntington disease-like mice
    Mary Y Heng
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Autophagy 6:1206-8. 2010
    ....