Neuronal specific Autophagy Signaling

Summary

Principal Investigator: Dale M Ando
Abstract: DESCRIPTION (provided by applicant): Autophagy is critical for neuron survival. In neurons, loss of autophagy leads to the formation of protein aggregates and neurodegeneration, both in vitro and in vivo after genetic disruption. Conversely, increasing autophagy ameliorates toxicity in a variety of neurodegenerative models. Thus, stimulation of autophagy has been proposed as a therapeutic strategy for neurodegenerative diseases characterized by the accumulation of unfolded proteins. mTOR is the canonical regulator of autophagy in non-neuronal cells, but our lab has shown that autophagy in primary neurons is not effectively regulated by mTOR. Drugs which induce mTOR- independent autophagy have been identified by our lab and others and could provide starting points for potential therapeutics in neurons. Although these drugs act on a variety of targets, a common activity that many share is that they reduce cytosolic calcium levels. We have novel data showing that this mechanism may also be responsible for mTOR-independent autophagy in neurons. Mimicking low cytosolic calcium in neurons using the calmodulin inhibitors fluphenazine and trifluoperazine leads to robust induction of mTOR- independent autophagy. However, the potential downstream mediator of cytosolic Ca2+-mediated autophagy is unknown. We have identified calcineurin, the only calcium sensitive phosphatase, as a potential regulator of neuronal autophagy downstream of low cytosolic calcium. Inhibition of calcineurin by two structurally distinct compounds, Cyclosporin A (CsA) and FK506, induced autophagy in a dose-dependent manner in primary neurons. Autophagy induction by CsA and FK506 is intriguing in light of previous data showing them to be protective in several neurodegenerative models. Our previous work has shown the neuroprotective role of autophagy, but it is unknown if the protective effects of CsA and FK506 are the result of autophagy induction. We hypothesize that calcineurin integrates high cytosolic Ca2+ levels to negatively regulate neuronal autophagy induction and that the protective effects of CsA/FK506 are mediated through autophagy induction by the inhibition of calcineurin. In Aim 1 we will determine whether calcineurin is sufficient to induce autophagy using more specific genetic means, and we will determine if neuronal autophagy is inhibited by activated calcineurin. In Aim 2 we will determine whether the protective effect of CsA/FK506 in HD is through autophagy by looking at whether the protective effect is abolished with inhibition of autophagy and whether the rate of autophagy in a neuron is predictive of neuronal death by apoptosis.
Funding Period: 2013-05-08 - 2014-11-07
more information: NIH RePORT

Detail Information

Research Grants30

  1. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  2. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  3. POLYGLUTAMINE CONFORMATION AND NEURODEGENERATION
    Steven M Finkbeiner; Fiscal Year: 2013
    ..This project is significant because it will elucidate pathogenic mechanisms and therapeutic targets for HD, as it did during the previous period;the findings should also be relevant to Alzheimer's and Parkinson's disease. ..
  4. ER SIGNAL AND CHAPERONE-MEDIATED AUTOPHAGY IN NEURONAL STRESS
    Zixu Mao; Fiscal Year: 2013
    ..This new mechanistic network should be highly relevant to the pathogenic process of neurological diseases and may aid the development of novel therapeutic strategies. ..
  5. Role of LIPL-4 in lysosomal lipolysis and aging
    LOUIS RENE LAPIERRE; Fiscal Year: 2013
    ..elegans. In summary, the K99/R00 grant represents a unique opportunity for me to learn new technologies and develop my professional skills to successfully transition into an independent scientist in aging research. ..
  6. The HD iPSC Consortium: Repeat Length Dependent Phenotypes for Assay Development
    Leslie Michels Thompson; Fiscal Year: 2013
    ..These cell lines will be an essential resource for academic groups and pharmaceutical companies for studying pathogenesis and for testing experimental therapeutics for HD. ..
  7. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....
  8. ALS-associated TDP-43 Aggregation: A Drosophila Model and A Role for Autophagy
    Keith A Hanson; Fiscal Year: 2013
    ..In addition, the Drosophila model described above will also be used to address this question in vivo. ..
  9. CYTOKINES IN GLIAL CELLS AND EAE BRAIN
    Inderjit Singh; Fiscal Year: 2013
    ..These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases. ..
  10. A New E3 Ligase Implicated in Protein Quality Control and Neurodegeneration
    Claudio A P Joazeiro; Fiscal Year: 2013
    ..abstract_text> ..
  11. Impaired Protein Degradation Pathways in Cardiac Proteinopathy
    Patrick M McLendon; Fiscal Year: 2013
    ..abstract_text> ..
  12. Histone deacetylase 6 and aggresome-associated neurodegeneration
    Tso Pang Yao; Fiscal Year: 2013
    ..By characterizing the mechanism and protein machinery that eliminate toxic protein aggregates and damaged mitochondria, we hope to identify new avenues for developing novel therapeutic approaches for treating neurodegenerative disease. ..
  13. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  14. The Pathogenesis of Facioscapulohumeral Muscular Dystrophy
    Stephen J Tapscott; Fiscal Year: 2013
    ..Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies. ..
  15. 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. ..
  16. Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration
    ROBERT JOSEPH SHMOOKLER REIS; Fiscal Year: 2013
    ..Proteins or modifications in either soluble or insoluble aggregates, which vary concordantly with neurotoxicity, become functional candidates ..
  17. TBI-Induced Cerebral Metabolic Depression and Recovery
    David A Hovda; Fiscal Year: 2013
    ..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
  18. 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. ..