Modulation of the PPAR-delta Signaling Pathway in Huntingtons Disease


Principal Investigator: Audrey S Dickey
Abstract: DESCRIPTION (provided by applicant): Huntington's disease (HD) is a relentlessly progressive autosomal dominant neurodegenerative disorder characterized by the development of involuntary movements, cognitive decline, and psychiatric illness (1). This polyglutamine disorder arises from a CAG trinucleotide-repeat expansion mutation in the coding region of the huntingtin (Htt) gene encoding an extended polyglutamine (polyQ) tract. Recent studies by our laboratory and others have shown that the mitochondrial dysfunction and metabolic deficits in HD result from transcriptional dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1[unreadable]) (2, 3). As a transcriptional regulator, PGC-1[unreadable] positively modulates several nuclear receptor transcription factors including the three Peroxisome Proliferator-Activated Receptor (PPAR) isoforms, [unreadable], ?, and [unreadable]. Of these, PPAR [unreadable] is the most abundantly expressed subtype in the central nervous system (CNS), although its functional relevance in this tissue has not been well defined (4, 5). With the discovery that retinoic acid binds to PPAR [unreadable] to mediate its previously well-documented pro-survival effects (6, 7), PPAR [unreadable] may be responsible for promoting a variety of survival / repair processes in neurons (8-10). Multiple components of the PPAR [unreadable] signaling transcriptional pathway have been elucidated in non-neuronal systems (6, 7). Pharmacologic (26) and genetic (27,28) activation of PPAR[unreadable] increases expression of genes involved in energy metabolism and mitochondrial biogenesis. The role of PPAR [unreadable] in neuronal function has not been well-defined, despite being expressed at levels higher than those in muscle (29). In Aim 1, I will test the hypothesis that polyglutamine-expanded huntingtin protein interferes with PPAR [unreadable] -mediated gene transcription, a perturbation that may contribute to the molecular pathology of Huntington's disease. In Aim 2, I will perform experiments in vitro and in vivo to test the hypothesis that enhancing the PPAR [unreadable] signaling pathway will ameliorate transcriptional dysfunction and neuronal degeneration seen in HD. By elucidating the role of the PPAR [unreadable] signaling pathway in HD, targets for treatment may be found not only for HD, but other polyglutamine diseases and neurodegenerative diseases.
Funding Period: 2012-09-01 - 2015-08-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants31

  1. Mitochondrial Porin in Bioenergetic Defects in Huntingtons Disease
    Nickolay Brustovetsky; Fiscal Year: 2013
  2. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
    Bruce L Miller; Fiscal Year: 2013
    ..abstract_text> ..
  4. Huntington's Disease: Analysis of Proteolysis
    ROBERT NORMAN O'BRIEN; Fiscal Year: 2013
    ..Finally, identification of novel proteins and pathways involved in neurotoxicity in HD will enable us to develop new drugs to slow or stop progression of neurodegeneration in HD patients. ..
  5. BDNF and Spine-Realted Disorders of Memory and Cognition
    Christine M Gall; Fiscal Year: 2013
    ..In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior. ..
  6. Regulation of CNS viral persistence
    Cornelia Bergmann; Fiscal Year: 2013
    ..Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response...
  7. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
  8. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mitochondrial Fission in Huntington's Disease
    ELLA R BOSSY-WETZEL; Fiscal Year: 2013
  10. Analysis of autophagy and mitochondrial homeostasis in a human iPS model of NCL
    JOHN FRANCOIS STAROPOLI; Fiscal Year: 2013
  11. The PPAR-delta pathway in neural function and Hungtington's disease neuropatholog
    Albert R La Spada; Fiscal Year: 2013
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  13. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  14. XIAP Gene Therapy in Huntington's Disease
    Michael G Kaplitt; Fiscal Year: 2013
    ..Given our promising preliminary data and recent use of gene therapy in human Parkinson's disease, this application may also facilitate development of XIAP gene therapy for human HD. ..
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  16. Investigation of TDP-43 Function and Toxicity in C. elegans
    Christopher D Link; Fiscal Year: 2013
    ..In this project we will use model systems to determine the functions of TDP-43 and how its deposition may cause neurodegeneration. ..
  17. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  18. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  19. mtDNA heteroplasmy in development and differentiation: an in-vitro approach
    RAJ RAGHAVENDRA RAO; Fiscal Year: 2013
    ..abstract_text> ..
  20. Regulation of Autophagy &Mitochondrial Recycling in Neuronal Cell Death
    Charleen T Chu; Fiscal Year: 2013
  21. Exploring Disease-Toxicant Interactions in a Human Huntington's Disease Model
    Andrew M Tidball; Fiscal Year: 2013
    ..As the principal investigator, I will have increased ownership of this research project and the freedom to take full advantage of my graduate training by reducing potential financial constraints. ..
  22. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013