Developing neuroprotective strategies for proteinopathy: a comparative modeling

Summary

Principal Investigator: Brian Kraemer
Affiliation: University of Washington
Country: USA
Abstract: DESCRIPTION (provided by applicant): The lesions seen in the degenerating neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) consist primarily of the TDP-43 protein. How aggregated TDP-43 protein causes neuronal dysfunction and neurodegeneration is poorly understood. However, mutations in the gene encoding TDP-43 cause some forms of familial ALS proving that abnormal TDP-43 causes neurodegeneration. Furthermore, TDP-43 positive pathological lesions appear in postmortem samples from several different neurodegenerative disorders including FTLD-U, ALS, Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies, and Guam amyotrophic lateral sclerosis/Parkinson's dementia. To model TDP-43 neurotoxicity in a simple animal model, we have transgenically expressed human TDP-43 protein in the neurons of the nematode worm, C. elegans. Expression of human TDP-43 in worm neurons causes neuronal dysfunction and accumulation of nuclear inclusions consisting of aggregated insoluble TDP-43 protein. We have previously reported a C. elegans model for the tau pathology seen in human tauopathy disorders including and AD. We propose to use the same methodologies to characterize the new model for TDP-43 proteinopathy with a focus on the mechanisms of TDP-43 mediated neurotoxicity and how the localization of TDP-43 protein alters its toxicity. The neuronal consequences of tau and TDP-43 protein expression will be investigated by profiling the transcriptional and post-translational responses to neurotoxicity. Transcriptional changes will be monitored using an mRNA tagging/microarray hybridization approach to identify genes up-regulated and down-regulated in response to neurotoxicity. The, genetic pathways that normally act to protect against the neurotoxic effects of TDP-43 will be identified using a genome-wide RNAi screening approach. Genes normally required for tau neurotoxicity will also be tested for their ability to modify the neurotoxicity of TDP-43. The long term goal of this work is to develop neuroprotective strategies for neurodegenerative disorders with TPD-43 and tau protein deposits. PUBLIC HEALTH RELEVANCE: Deposits of abnormally folded aggregated protein are found in a number of disorders affecting the nervous system including Alzheimer's disease and amyotrophic lateral sclerosis. We have generated different animal models for the nerve cell death seen in these disorders using the worm, C. elegans to understand how protein misfolding can causes disease. Our current work focuses on the newly identified aggregating protein TDP-43, a protein that forms misfolded protein deposits in many different nervous system disorders.
Funding Period: ----------------2009 - ---------------2014-
more information: NIH RePORT

Top Publications

  1. pmc Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis
    Irene G Salado
    Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Med Chem 57:2755-72. 2014
  2. pmc A High-Content Screen Identifies Novel Compounds That Inhibit Stress-Induced TDP-43 Cellular Aggregation and Associated Cytotoxicity
    Justin D Boyd
    1Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women s Hospital and Harvard Medical School, Cambridge, MA, USA
    J Biomol Screen 19:44-56. 2014
  3. pmc Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)
    Olena Korvatska
    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
    Hum Mol Genet 22:3259-68. 2013
  4. pmc CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration
    Nicole F Liachko
    Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA Department of Medicine, University of Washington, Seattle, WA
    Ann Neurol 74:39-52. 2013
  5. pmc Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity
    Allyson V McCormick
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
    Biol Psychiatry 73:464-71. 2013
  6. doi Potential neuroprotective strategies against tauopathy
    Jeanna M Wheeler
    Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA
    Biochem Soc Trans 40:656-60. 2012
  7. pmc Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation
    Guy R Watkins
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Biol Chem 287:24207-15. 2012
  8. pmc Truncation of tau at E391 promotes early pathologic changes in transgenic mice
    Pamela J McMillan
    Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
    J Neuropathol Exp Neurol 70:1006-19. 2011
  9. pmc MSUT2 is a determinant of susceptibility to tau neurotoxicity
    Chris R Guthrie
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA
    Hum Mol Genet 20:1989-99. 2011
  10. pmc Proteasome inhibition drives HDAC6-dependent recruitment of tau to aggresomes
    Chris R Guthrie
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
    J Mol Neurosci 45:32-41. 2011

Scientific Experts

  • Brian Kraemer
  • Chris R Guthrie
  • Nicole F Liachko
  • Jeanna M Wheeler
  • James B Leverenz
  • Pamela J McMillan
  • Irene G Salado
  • Justin D Boyd
  • Olena Korvatska
  • Allyson V McCormick
  • Thomas D Bird
  • Guy R Watkins
  • Daniel I Perez
  • Benjamin Wolozin
  • Magalie Lecourtois
  • Atsushi Ebata
  • Miriam Redondo
  • John B Concannon
  • Marcie A Glicksman
  • Min Liu
  • Nava Zaarur
  • Concepcion Perez
  • Laetitia Miguel
  • J Peter Lee-Armandt
  • Murilo L Bello
  • Carmen Gil
  • Marisa S Feiler
  • Ana Martinez
  • Evan E Eichler
  • Wendy H Raskind
  • Joseph Chuang
  • Tim Strovas
  • Randall T Moon
  • Nicholas S Strand
  • Deborah A Nickerson
  • Emre Karakoc
  • J Lynne Greenup
  • Jason D Berndt
  • Ignacio F Mata
  • Dong Hui Chen
  • Konstantin Kiianitsa
  • Emily Bonkowski
  • Cyrus P Zabetian
  • Benjamin W Spiller
  • Matthew D Mazalouskas
  • Rey J Gomez
  • Ning Wang
  • Brian E Wadzinski
  • Susann Schweiger
  • Gerard Schellenberg
  • Murray Raskind
  • Linda Robinson
  • Lynne Greenup

Detail Information

Publications13

  1. pmc Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis
    Irene G Salado
    Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Med Chem 57:2755-72. 2014
    ..Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved. ..
  2. pmc A High-Content Screen Identifies Novel Compounds That Inhibit Stress-Induced TDP-43 Cellular Aggregation and Associated Cytotoxicity
    Justin D Boyd
    1Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women s Hospital and Harvard Medical School, Cambridge, MA, USA
    J Biomol Screen 19:44-56. 2014
    ..The hits from this assay will be useful for elucidating regulation of TDP-43, stress granule response, and possible ALS therapeutics. ..
  3. pmc Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)
    Olena Korvatska
    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
    Hum Mol Genet 22:3259-68. 2013
    ..Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations. ..
  4. pmc CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration
    Nicole F Liachko
    Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA Department of Medicine, University of Washington, Seattle, WA
    Ann Neurol 74:39-52. 2013
    ..Dual phosphorylation of TDP-43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP-43-specific kinases are candidate targets for intervention...
  5. pmc Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity
    Allyson V McCormick
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
    Biol Psychiatry 73:464-71. 2013
    ..Presently no effective disease-modifying treatments exist for tauopathies...
  6. doi Potential neuroprotective strategies against tauopathy
    Jeanna M Wheeler
    Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA
    Biochem Soc Trans 40:656-60. 2012
    ..elegans tauopathy model and subsequently shown to modify tau toxicity in mammalian cell culture via the effects on autophagy pathways. MSUT2 represents a potential drug target for prevention of tau-related neurodegeneration...
  7. pmc Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation
    Guy R Watkins
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Biol Chem 287:24207-15. 2012
    ..These findings indicate that regulated inter-domain cleavage controls the dual functions of α4, and dysregulation of α4 cleavage may contribute to Opitz syndrome and Alzheimer disease...
  8. pmc Truncation of tau at E391 promotes early pathologic changes in transgenic mice
    Pamela J McMillan
    Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
    J Neuropathol Exp Neurol 70:1006-19. 2011
    ..In addition, these mice exhibit atypical neuritic tau immunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes in tau proteolysis can initiate tauopathy...
  9. pmc MSUT2 is a determinant of susceptibility to tau neurotoxicity
    Chris R Guthrie
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA
    Hum Mol Genet 20:1989-99. 2011
    ..Thus, neuroprotective strategies targeting MSUT2 may be of therapeutic interest for tauopathy disorders...
  10. pmc Proteasome inhibition drives HDAC6-dependent recruitment of tau to aggresomes
    Chris R Guthrie
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
    J Mol Neurosci 45:32-41. 2011
    ....
  11. pmc Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy
    Nicole F Liachko
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
    J Neurosci 30:16208-19. 2010
    ..Furthermore, phosphorylation of TDP-43 at serine residues 409/410 drives mutant TDP-43 toxicity. This model provides a tractable system for additional dissection of the cellular and molecular mechanisms underlying TDP-43 neuropathology...
  12. pmc The role of MSUT-2 in tau neurotoxicity: a target for neuroprotection in tauopathy?
    Jeanna M Wheeler
    Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, 1660 S Colombian Way, Seattle, WA 98108, USA
    Biochem Soc Trans 38:973-6. 2010
    ..The identification of sut-2 as a gene required for tau neurotoxicity in C. elegans suggests new neuroprotective strategies targeting MSUT-2 that may be effective in modulating tau neurotoxicity in human tauopathy disorders...
  13. pmc Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis
    Brian C Kraemer
    Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
    Acta Neuropathol 119:409-19. 2010
    ..Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons...