Defective nuclear FGFR1 signaling - a new model for PD

Summary

Principal Investigator: Michal K Stachowiak
Abstract: In Parkinson Disease (PD) the content of fibroblast growth factor-2 (FGF-2) in dopamine neurons in substantia nigra pars compacta (Snc) becomes depleted prior to cell degeneration. In the Snc the most abundant are the HMW non-released isoforms of FGF-2 that localize almost exclusively in the cell nucleus. Functions of nuclear FGF-2 and the significance of its depletion in Snc neurons in PD patients remain unknown. We have described a new Integrative Nuclear FGF41 Signaling (INFS) pathway through which diverse extracellular factors and intracellular cAMP and Protein Kinase C regulate growth and survival of neuronal cells and proliferation of astrocytes. These broad functions are likely to involve regulation of several gene programs. This INFS is initiated by the activation of the FGF-2 and FGF receptor-1 (FGFR1) genes followed by transfer of FGFR1 and FGF-2 proteins directly from the cytoplasm to the cell nucleus: Nuclear FGFR1, interacts with Ribosomal S6 Kinase-1 (RSK-1) and stimulate transcription of different genes. The INFS regulates axonal and dendritic growth in cultured neurons and resistance to 6-hydroxydopamine in PC12 cells. Polyetheleneimine-mediated in vivo transfection of dominant negative of the FGFR1 mutant [FGFR1(TK-) lacking tyrosine kinase domain] into the rat Snc caused a delayed loss of tyrosine hydrosxylase expressing neurons and depletion of striatal dopamine. This indicated that TGFR1 signaling is essential also for the long term survival of DA neurons and impaired INFS (i.e. due to a depletion of nuclear FGF-2) may be a common underlying cause for the neuronal degeneration in PD. To elucidate the role of INFS in survival regeneration and functional plasticity of the rat Snc DA neurons, we will use PEI-mediated transfection of FGFR1 and RSK-1 mutants, in vivo, into the adult rat brain. These experiments will establish a new, gene- transfer-based model for common PD and may identify new molecular targets for gene-transfer and pharmacological therapies for the PD and related neurodegenerative disorders. The specific Aims are: (1) To determine time courser and characterize neurodegenerative changes in the nigrostriatal pathway caused by transfection of FGFR (TK-) and establish whether impaired FGFR signaling directly in the cell nucleus is responsible for the observed effects of FGFR1 (TK-), (2) To identify types of genes regulated by nuclear FGFR1 in rat Snc and whether over- expression of active RSK-1 counteracts the FGFR1(TK)-induced changes in gene expression and degeneration of the nigrostriatal pathway, and (3) To determine whether direct stimulation of nuclear FGFR-1 signaling may attenuate degenerative changes in the nigrostriatal pathway caused by neurotoxin 6-hydroxydopamine and/or promote regeneration.
Funding Period: 2002-02-01 - 2005-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Transfection of tyrosine kinase deleted FGF receptor-1 into rat brain substantia nigra reduces the number of tyrosine hydroxylase expressing neurons and decreases concentration levels of striatal dopamine
    Thomas D Corso
    Molecular and Structural Neurobiology and Gene Therapy Program, University at Buffalo, SUNY, Buffalo, NY 14260, USA
    Brain Res Mol Brain Res 139:361-6. 2005
  2. pmc Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain
    Dhruba J Bharali
    Institute for Lasers, Photonics, and Biophotonics, Department of Chemistry, State University of New York, Buffalo, NY 14260, USA
    Proc Natl Acad Sci U S A 102:11539-44. 2005
  3. ncbi Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methods
    Thomas D Corso
    Molecular and Structural Neurobiology and Gene Therapy Program, SUNY, University at Buffalo, Buffalo, NY 14214, USA
    Folia Morphol (Warsz) 64:130-44. 2005
  4. ncbi Neural stem-like cell line derived from a nonhematopoietic population of human umbilical cord blood
    Leonora Buzanska
    NeuroRepair Department, Medical Research Center, Warsaw, Poland
    Stem Cells Dev 15:391-406. 2006

Detail Information

Publications4

  1. ncbi Transfection of tyrosine kinase deleted FGF receptor-1 into rat brain substantia nigra reduces the number of tyrosine hydroxylase expressing neurons and decreases concentration levels of striatal dopamine
    Thomas D Corso
    Molecular and Structural Neurobiology and Gene Therapy Program, University at Buffalo, SUNY, Buffalo, NY 14260, USA
    Brain Res Mol Brain Res 139:361-6. 2005
    ..Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease...
  2. pmc Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain
    Dhruba J Bharali
    Institute for Lasers, Photonics, and Biophotonics, Department of Chemistry, State University of New York, Buffalo, NY 14260, USA
    Proc Natl Acad Sci U S A 102:11539-44. 2005
    ....
  3. ncbi Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methods
    Thomas D Corso
    Molecular and Structural Neurobiology and Gene Therapy Program, SUNY, University at Buffalo, Buffalo, NY 14214, USA
    Folia Morphol (Warsz) 64:130-44. 2005
    ....
  4. ncbi Neural stem-like cell line derived from a nonhematopoietic population of human umbilical cord blood
    Leonora Buzanska
    NeuroRepair Department, Medical Research Center, Warsaw, Poland
    Stem Cells Dev 15:391-406. 2006
    ..These cells should further our understanding of the regulatory mechanisms involved in NSC self-renewal and differentiation...