TDP 43

Summary

Gene Symbol: TDP 43
Description: TAR DNA binding protein
Alias: ALS10, TDP-43, TAR DNA-binding protein 43, TAR DNA-binding protein-43
Species: human

Top Publications

  1. ncbi Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
    Manuela Neumann
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Science 314:130-3. 2006
  2. pmc TDP-43 regulates its mRNA levels through a negative feedback loop
    Youhna M Ayala
    Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    EMBO J 30:277-88. 2011
  3. doi TDP-43 mutation in familial amyotrophic lateral sclerosis
    Akio Yokoseki
    Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
    Ann Neurol 63:538-42. 2008
  4. doi Nuclear factor TDP-43 can affect selected microRNA levels
    Emanuele Buratti
    International Centre for Genetic Engineering and Biotechnology ICGEB, Trieste, Italy
    FEBS J 277:2268-81. 2010
  5. pmc Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA
    Sang Hwa Kim
    Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Biol Chem 285:34097-105. 2010
  6. pmc Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection
    S Eréndira Avendaño-Vázquez
    International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    Genes Dev 26:1679-84. 2012
  7. pmc A "two-hit" hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport
    G Scott Pesiridis
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 286:18845-55. 2011
  8. doi Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43
    Takashi Nonaka
    Department of Molecular Neurobiology, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan
    Hum Mol Genet 18:3353-64. 2009
  9. pmc TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97
    Gillian P Ritson
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 30:7729-39. 2010
  10. pmc ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS
    Shuo Chien Ling
    Ludwig Institute for Cancer Research and Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093 0670, USA
    Proc Natl Acad Sci U S A 107:13318-23. 2010

Research Grants

  1. TDP-43 acetylation as a pathogenic modification in ALS &related proteinopathies
    TODD JONATHAN COHEN; Fiscal Year: 2013
  2. ALS therapies and genomics for mutant TDP-43 and TLS/FUS
    Don W Cleveland; Fiscal Year: 2010
  3. Defining Mechanisms of TDP-43 Ubiquitination for Quality Control and Aggregation
    ERIC BERNARD DAMMER; Fiscal Year: 2012
  4. Sami Barmada; Fiscal Year: 2015
  5. Characterizing TDP-43 isoforms in neurodegenerative disease
    NICHOLAS THOMAS SEYFRIED; Fiscal Year: 2010
  6. Phage Display Investigations of TDP-43
    RAYMOND PHILIP contact ROOS; Fiscal Year: 2010
  7. Progranulin, TAR DNA binding protein-43 and Cell Death
    Leonard Petrucelli; Fiscal Year: 2009
  8. Amit Berson; Fiscal Year: 2015
  9. Small Molecule Probes for TAR DNA Binding Protein 43_TDP-43
    Allen B Reitz; Fiscal Year: 2012
  10. Leonard Petrucelli; Fiscal Year: 2014

Detail Information

Publications235 found, 100 shown here

  1. ncbi Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
    Manuela Neumann
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Science 314:130-3. 2006
    ..TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders...
  2. pmc TDP-43 regulates its mRNA levels through a negative feedback loop
    Youhna M Ayala
    Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    EMBO J 30:277-88. 2011
    ..Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis...
  3. doi TDP-43 mutation in familial amyotrophic lateral sclerosis
    Akio Yokoseki
    Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
    Ann Neurol 63:538-42. 2008
    ..Our findings provide a new insight into the molecular pathogenesis of ALS...
  4. doi Nuclear factor TDP-43 can affect selected microRNA levels
    Emanuele Buratti
    International Centre for Genetic Engineering and Biotechnology ICGEB, Trieste, Italy
    FEBS J 277:2268-81. 2010
    ..Using microarray data and real-time PCR we have also identified several candidate transcripts whose expression levels are selectively affected by these TDP-43-miRNA interactions...
  5. pmc Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA
    Sang Hwa Kim
    Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Biol Chem 285:34097-105. 2010
    ....
  6. pmc Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection
    S Eréndira Avendaño-Vázquez
    International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    Genes Dev 26:1679-84. 2012
    ..Overall, we uncover complex interplay between transcription, splicing, and 3' end processing to effect autoregulation of TDP-43...
  7. pmc A "two-hit" hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport
    G Scott Pesiridis
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 286:18845-55. 2011
    ..Our data support a "two-hit" mechanism of CTF aggregation dependent on TDP-43 cleavage...
  8. doi Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43
    Takashi Nonaka
    Department of Molecular Neurobiology, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan
    Hum Mol Genet 18:3353-64. 2009
    ....
  9. pmc TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97
    Gillian P Ritson
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 30:7729-39. 2010
    ..We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis...
  10. pmc ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS
    Shuo Chien Ling
    Ludwig Institute for Cancer Research and Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093 0670, USA
    Proc Natl Acad Sci U S A 107:13318-23. 2010
    ..Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS...
  11. doi Structural determinants of the cellular localization and shuttling of TDP-43
    Youhna M Ayala
    International Centre for Genetic Engineering and Biotechnology ICGEB, 34012 Trieste, Italy
    J Cell Sci 121:3778-85. 2008
    ....
  12. pmc Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43
    Yoshinori Nishimoto
    Department of Neurology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku ku, Tokyo 160 8582, Japan
    J Biol Chem 285:608-19. 2010
    ..Our findings provide new biological and pathological insight into the development of TDP-43 proteinopathies...
  13. pmc Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins
    Shoji Watanabe
    Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 351 0198, Japan
    J Biol Chem 288:3641-54. 2013
    ..These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis...
  14. doi Progressive motor weakness in transgenic mice expressing human TDP-43
    Nancy R Stallings
    Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA
    Neurobiol Dis 40:404-14. 2010
    ..Transgenic mouse lines expressing untagged mutant and wild type TDP-43 under the same promoter represent a powerful new model system for studying TDP-43 proteinopathies in vivo...
  15. pmc TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression
    Youhna M Ayala
    International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy
    Proc Natl Acad Sci U S A 105:3785-9. 2008
    ..Our results identify a regulatory target of TDP-43 and show that TDP-43 depletion has important consequences in essential metabolic processes in human cells...
  16. pmc TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes
    Yukio Kawahara
    Laboratory of RNA Function, Graduate School of Medicine, Osaka University, Osaka 565 0871, Japan
    Proc Natl Acad Sci U S A 109:3347-52. 2012
    ..These results support a previously uncharacterized role for TDP-43 in posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm...
  17. doi Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies
    Tetsuaki Arai
    Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2 1 8 Kamikitazawa, Setagaya Ku, Tokyo 156 8585, Japan
    Acta Neuropathol 117:125-36. 2009
    ..There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and alpha-synuclein...
  18. pmc Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43
    Rodrigo A Fuentealba
    Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 285:26304-14. 2010
    ....
  19. doi Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis
    H Daoud
    Centre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, University of Montreal, Montreal, Quebec, Canada
    J Med Genet 46:112-4. 2009
    ..We screened the TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS...
  20. doi UG repeats/TDP-43 interactions near 5' splice sites exert unpredictable effects on splicing modulation
    Monica Passoni
    International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
    J Mol Biol 415:46-60. 2012
    ..The general rule that can be drawn at the moment is that the importance of UG repeats near 5' splice sites should always be experimentally validated on a case-by-case basis...
  21. pmc TDP-43 skeins show properties of amyloid in a subset of ALS cases
    John L Robinson
    Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer s Disease Core Center, Institute on Aging, Perelman School of Medicine at the University of Pennsylvania, Maloney Building, 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104 4283, USA
    Acta Neuropathol 125:121-31. 2013
    ....
  22. pmc Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43)
    Eva Bentmann
    Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, Munchen, Germany
    J Biol Chem 287:23079-94. 2012
    ....
  23. pmc Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis
    Nicola J Rutherford
    Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America
    PLoS Genet 4:e1000193. 2008
    ....
  24. pmc TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis
    Rita J Guerreiro
    Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland, United States of America
    PLoS ONE 3:e2450. 2008
    ..Recently, mutations in TARDBP have been linked to familial and sporadic ALS...
  25. doi Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell
    W Duan
    Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
    Neuroscience 169:1621-9. 2010
    ..How mutant TDP-43 reduces expression of HO-1 and prevents sulforaphane from activating Nrf2 signaling remains to be investigated...
  26. doi High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis
    Lucia Corrado
    Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy
    Hum Mutat 30:688-94. 2009
    ..In conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that mutations may affect the stability of the protein even in nonneuronal tissues...
  27. 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...
  28. pmc Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice
    Ya Fei Xu
    Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, USA
    Mol Neurodegener 6:73. 2011
    ..Such findings support a direct link between altered TDP-43 function and neurodegeneration...
  29. pmc Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis
    Edward Pokrishevsky
    Brain Research Centre, University of British Columbia, Vancouver, Canada
    PLoS ONE 7:e35050. 2012
    ..In this study, we tested the hypothesis that FUS/TLS and TDP43 gain new pathogenic functions upon aberrant accumulation in the cytosol that directly or indirectly include misfolding of SOD1...
  30. pmc Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones
    Maria Udan-Johns
    Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Hum Mol Genet 23:157-70. 2014
    ....
  31. doi TDP-43 Phosphorylation by casein kinase Iε promotes oligomerization and enhances toxicity in vivo
    Darshana K Choksi
    Department of Neuroscience and Cell Biology
    Hum Mol Genet 23:1025-35. 2014
    ..These data identify CKIε as a potent TDP-43 kinase in vivo and implicate oligomeric species as the toxic entities in TDP-43 proteinopathies. ..
  32. pmc Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS
    Andrew C Elden
    Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nature 466:1069-75. 2010
    ..Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies...
  33. doi HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice
    Yansu Guo
    Department of Neurology, The Second Hospital of Hebei Medical University, Hebei 050000, China
    Brain Res 1460:88-95. 2012
    ..Increased TDP-43 accumulation in the myenteric nerve plexus and increased thickness of muscular layer of colon were related to the intestinal dysfunction...
  34. pmc TDP-43 aggregation in neurodegeneration: are stress granules the key?
    Colleen M Dewey
    Department of Neuroscience, The University of Texas Southwestern Medical Center at Dallas, USA
    Brain Res 1462:16-25. 2012
    ..This article is part of a Special Issue entitled: RNA-Binding Proteins...
  35. doi Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling
    Paola Origone
    Department of Oncology, Biology and Genetics, University of Genoa and U O Medical Genetics of Azienda Ospedaliera, Universitaria S Martino di Genova, Italy
    Amyotroph Lateral Scler 11:223-7. 2010
    ..The present study was aimed to enlarge the Italian ALS sample analysed for TARDBP gene mutations...
  36. pmc Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis
    Hui Ling Xiong
    Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China
    BMC Med Genet 11:8. 2010
    ..TARDBP mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between TARDBP mutations and Chinese patients with ALS...
  37. pmc Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene
    Adriano Chio
    Department of Neuroscience, University of Torino, Via Cherasco 15, Turin, Italy
    Arch Neurol 68:594-8. 2011
    ..To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations...
  38. pmc A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro
    Matthew J Winton
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    FEBS Lett 582:2252-6. 2008
    ..Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates...
  39. doi Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS
    Yuki Inukai
    Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2 1 8 Kamikitazawa, Setagaya Ku, Tokyo 156 8585, Japan
    FEBS Lett 582:2899-904. 2008
    ..Analysis of postmortem changes of TDP-43 revealed that the amounts of Sarkosyl-insoluble, urea-soluble full-length TDP-43 and a 35kDa N-terminal fragment increased time-dependently...
  40. pmc TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
    Iga Wegorzewska
    Department of Neurology and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 106:18809-14. 2009
    ....
  41. ncbi TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease
    Linda K Kwong
    Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP, Philadelphia, PA, 19104 4283, USA
    Acta Neuropathol 114:63-70. 2007
    ....
  42. pmc Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation
    Matthew J Winton
    Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 283:13302-9. 2008
    ..Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43...
  43. pmc Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping
    E Buratti
    International Centre for Genetic Engineering and Biotechnology ICGEB, Padriciano 99, 34012 Trieste, Italy
    EMBO J 20:1774-84. 2001
    ..The clinical and biological relevance of this finding in vivo is demonstrated by our characterization of a CF patient carrying a TG10T9(DeltaF508)/TG13T3(wt) genotype leading to a disease-causing high proportion of exon 9 skipping...
  44. doi Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells
    Takashi Nonaka
    Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2 1 8 Kamikitazawa, Setagaya ku 156 8585, Tokyo, Japan
    FEBS Lett 583:394-400. 2009
    ..Our results suggest that intracellular localization of TDP-43 and proteasomal function may be involved in inclusion formation and neurodegeneration in TDP-43 proteinopathies...
  45. pmc TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity
    Brian S Johnson
    Department of Cell and Developmental Biology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 284:20329-39. 2009
    ..Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations...
  46. doi The N-terminus of TDP-43 promotes its oligomerization and enhances DNA binding affinity
    Chung Ke Chang
    Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
    Biochem Biophys Res Commun 425:219-24. 2012
    ..An unidentified structural domain in the N-terminus is also disclosed. Our findings provide insights into the N-terminal domain function of TDP-43...
  47. pmc TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing
    Jayarama Krishnan Bose
    Institute of Molecular Medicine, National Taiwan University, Taipei 106, Taiwan
    J Biol Chem 283:28852-9. 2008
    ..Our data further evidence TDP-43 as a multifunctional RNA-binding protein for a diverse set of cellular activities...
  48. doi Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis
    Masaki Kamada
    Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1 2 3 Kasumi, Minami Ku, Hiroshima 734 8553, Japan
    J Neurol Sci 284:69-71. 2009
    ..It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation...
  49. doi Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation
    Mauricio Budini
    International Centre for Genetic Engineering and Biotechnology ICGEB 34012 Trieste, Italy
    Brain Res 1462:139-50. 2012
    The overview of TDP 43 functions immediately disclose a number of open questions regarding its pathological role...
  50. pmc Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations
    ZhiJun Zhang
    Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
    PLoS ONE 8:e76055. 2013
    ..These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts. ..
  51. doi Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
    Hsiang Yu Chang
    1 Garage Brain Science, Taichung 413, Taiwan 2 Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 404, Taiwan
    Nat Commun 4:2757. 2013
    ..In summary, our study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation. ..
  52. pmc Folding of the RNA recognition motif (RRM) domains of the amyotrophic lateral sclerosis (ALS)-linked protein TDP-43 reveals an intermediate state
    Brian C Mackness
    From the Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
    J Biol Chem 289:8264-76. 2014
    ..The intermediate state may also serve as a molecular hazard linking productive folding and function with pathological misfolding and aggregation that may contribute to disease. ..
  53. pmc Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins
    Yari Carlomagno
    Department of Neuroscience, Maya Clinic, Jacksonville, Florida, United States of America
    PLoS ONE 9:e90452. 2014
    ..The lack of methodology to produce soluble full length TDP-43 and recapitulate this polymerization into filaments as observed in disease has limited our understanding of these pathogenic cascades...
  54. doi Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS
    Yukio Fujita
    Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
    J Neurol Sci 269:30-4. 2008
    ..These results suggest that neurons with abnormal TDP-43 immunoreactivities are associated with dysfunction of the secretory pathway in motor neurons...
  55. doi TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies
    Montse Olive
    Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL Hospital Universitari de Bellvitge, Spain
    J Neuropathol Exp Neurol 68:262-73. 2009
    ....
  56. doi Identification of casein kinase-1 phosphorylation sites on TDP-43
    Fuyuki Kametani
    Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan
    Biochem Biophys Res Commun 382:405-9. 2009
    ..Interestingly, 18 of them were located in the C-terminal glycine-rich region of TDP-43. Our results indicate that CK1-mediated phosphorylation may play a role in the pathogenesis of these diseases...
  57. doi Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS)
    Kathryn Volkening
    Molecular Brain Research Group, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada N6A 5K8
    Brain Res 1305:168-82. 2009
    ..These data suggest that NFL mRNA processing is fundamentally altered in ALS spinal motor neurons to favour compartmentalization within both stress granules and P-bodies, and that TDP-43 plays a fundamental role in this process...
  58. pmc Higher order arrangement of the eukaryotic nuclear bodies
    I Fan Wang
    Institute of Molecular Biology, Academia Sinica, National Taiwan University, Taipei, Taiwan 115, Republic of China
    Proc Natl Acad Sci U S A 99:13583-8. 2002
    ..Furthermore, TB sometimes appears to be the bridge of two or more of these other nuclear bodies. Our data suggest the existence of a hierarchy and possibly functional arrangement of the nuclear bodies within the eukaryotic nuclei...
  59. doi TDP-43 dimerizes in human cells in culture
    Yuki Shiina
    Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, 2 522 1 Noshio Kiyose, Tokyo, 204 8588, Japan
    Cell Mol Neurobiol 30:641-52. 2010
    ..These results suggest that the 86-kDa band represents dimerized TDP-43 expressed constitutively in normal cells under physiological conditions...
  60. ncbi Familial ALS with G298S mutation in TARDBP: a comparison of CSF tau protein levels with those in sporadic ALS
    Ichiro Nozaki
    Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
    Intern Med 49:1209-12. 2010
    ..The elevated CSF-tau level might be related to the damage of neurons exhibiting a large number of TDP-43 inclusions in familial ALS with this mutation...
  61. doi Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing
    Mei Xia Che
    State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai 200031, China
    FASEB J 25:2344-53. 2011
    ..This suggests that fragmentation of TDP-43 leads to cellular redistribution, inclusion body formation, and altered RNA processing, which are implicated in the molecular pathogenesis of ALS and FTLD...
  62. ncbi Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease
    Emanuele Buratti
    International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
    Front Biosci 13:867-78. 2008
    ..The aim of this work is to provide the basic facts about TDP-43 an assessment of the multiple functions ascribed to this protein...
  63. doi Epitope mapping of 2E2-D3, a monoclonal antibody directed against human TDP-43
    Hai Xin Zhang
    Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki 036 8562, Japan
    Neurosci Lett 434:170-4. 2008
    ..These findings suggest that 2E2-D3 is a useful antibody for the characterization of mouse lines transgenic for human TDP-43...
  64. pmc Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease
    Wen Lang Lin
    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA
    J Neuropathol Exp Neurol 68:1167-76. 2009
    ..These data suggest that these processes are astrocytic end-feet with abnormal TDP-43 fibrillary inclusions. The significance of this novel TDP-43 microvasculopathy on blood-brain barrier integrity warrants further investigation...
  65. pmc TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy
    Ann C McKee
    Geriatric Research Education Clinical Center, Bedford Veterans Administration Hospital, Bedford, Massachusetts 01730, USA
    J Neuropathol Exp Neurol 69:918-29. 2010
    ..This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease...
  66. pmc Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs
    S H Ou
    Department of Medicine, University of Texas Southwestern Medical Center at Dallas 75235, USA
    J Virol 69:3584-96. 1995
    ..These results indicate that TDP-43 is capable of modulating both in vitro and in vivo HIV-1 gene expression by either altering or blocking the assembly of transcription complexes that are capable of responding to Tat...
  67. ncbi TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing
    Emanuele Buratti
    International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    J Biol Chem 280:37572-84. 2005
    ..Finally, through splicing complex analysis, we show that splicing inhibition mediated by TDP-43 occurs at the earliest stages of spliceosomal assembly...
  68. pmc Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies
    Kunihiro Uryu
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    J Neuropathol Exp Neurol 67:555-64. 2008
    ..These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis...
  69. pmc Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis
    Mohammad Salajegheh
    Department of Neurology, Division of Neuromuscular Disease, Brigham and Women s Hospital, and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA
    Muscle Nerve 40:19-31. 2009
    ..TDP-43 could be one of many nucleic acid binding proteins that are abnormally present in IBM sarcoplasm. They could potentially interfere with the normal function of extranuclear RNAs that maintain myofiber protein production...
  70. pmc Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments
    Yong Jie Zhang
    Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    Mol Neurodegener 5:33. 2010
    ..However, little is known regarding the pathways responsible for the degradation of these fragments and how their phosphorylation contributes to the pathogenesis of disease...
  71. doi RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS
    Shangxi Xiao
    Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, 6 Queen s Park Crescent West, Toronto, Ontario, Canada M5S 3H2
    Mol Cell Neurosci 47:167-80. 2011
    ..Of eight genes meeting these criteria, five were differentially spliced in ALS versus control. This supports the premise that abnormalities of TDP-43 in ALS are reflected in changes of RNA processing...
  72. doi TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations
    R Del Bo
    Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, Milan, Italy
    Eur J Neurol 16:727-32. 2009
    ..Mutations in the TARDBP gene, which codes for TDP-43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases...
  73. pmc Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6
    Fabienne C Fiesel
    Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tubingen, Germany
    EMBO J 29:209-21. 2010
    ..In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis...
  74. doi Loss of TDP-43 causes age-dependent progressive motor neuron degeneration
    Yohei Iguchi
    Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466 8550, Japan
    Brain 136:1371-82. 2013
    ....
  75. pmc Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast
    Ralf J Braun
    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    J Biol Chem 286:19958-72. 2011
    ..These data demonstrate that mitochondria and oxidative stress are important to TDP-43-triggered cell death in yeast and may suggest a similar role in human TDP-43 pathologies...
  76. doi Novel TARDBP mutations in Nordic ALS patients
    Huei Hsin Chiang
    Department of NVS, KI Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden
    J Hum Genet 57:316-9. 2012
    ..The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries...
  77. pmc Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction
    Ashley Cannon
    Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
    Acta Neuropathol 123:807-23. 2012
    ..Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies...
  78. ncbi Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases
    Hanae Nakashima-Yasuda
    Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP Maloney 3rd Floor, Philadelphia, PA 19104 4283, USA
    Acta Neuropathol 114:221-9. 2007
    ..This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders...
  79. ncbi TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan
    Akira Tamaoka
    Department of Neurology, Doctoral Program in Medical Sciences for Control of Pathological Processes, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba
    Intern Med 49:331-4. 2010
    ..In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated...
  80. pmc Rethinking ALS: the FUS about TDP-43
    Clotilde Lagier-Tourenne
    Department of Cellular and Molecular Medicine, University of California San Diego, Ludwig Institute for Cancer Research, La Jolla, CA 92093 0670, USA
    Cell 136:1001-4. 2009
    ..TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as a key event in ALS pathogenesis...
  81. doi TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea
    Gabor G Kovacs
    Institute of Neurology, Medical University of Vienna, Vienna, Austria
    Mov Disord 24:1843-7. 2009
    ..This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS...
  82. pmc TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration
    Hans Wils
    Department of Molecular Genetics, VIB, B 2610 Antwerpen, Belgium
    Proc Natl Acad Sci U S A 107:3858-63. 2010
    ..These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function...
  83. doi FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS
    Ching Paio Tsai
    Department of Neurology, National Yang Ming University School of Medicine, Taipei, Taiwan
    Neurobiol Aging 32:553.e13-21. 2011
    ....
  84. pmc Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
    Lionel M Igaz
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Clin Invest 121:726-38. 2011
    ..Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons...
  85. doi Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
    Victoria Ayala
    Grup de Fisiopatologia Metabòlica, Departament de Medicina Experimental, Universitat de Lleida IRBLLEIDA, Lleida, Spain
    Acta Neuropathol 122:259-70. 2011
    ..These results demonstrate that cellular stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS...
  86. doi Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site
    Yoshiaki Furukawa
    Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama, Japan
    Biochim Biophys Acta 1812:1577-83. 2011
    ..Molecular properties of TDP-43 fragments thus significantly depend upon its cleavage site, which might reflect distinct molecular pathologies among sub-types of TDP-43 proteinopathies...
  87. doi Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43
    Makoto Urushitani
    Unit for Neurobiology and Therapeutics, Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan
    J Neurosci Res 88:784-97. 2010
    ..Further clarification of the mechanism of polyubiquitination of TDP-43 and the role of autophagosomes may help in understanding and treating ALS...
  88. ncbi Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS
    Ilse Gijselinck
    Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Belgium
    Neurobiol Aging 30:1329-31. 2009
    ..Our data implicate that TDP-43 has no primary genetic role in the pathophysiological mechanisms underlying central nervous system neurodegeneration in these diseases...
  89. ncbi Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9
    E Buratti
    International Center for Genetic Engineering and Biotechnology ICGEB 34012 Trieste, Italy
    J Biol Chem 276:36337-43. 2001
    ..In particular, the highly conserved Phe residues in the first RRM region play a key role in nucleic acid recognition...
  90. ncbi TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein
    Michael J Strong
    Cell Biology Research Group, Robarts Research Institute, London, Ontario, Canada
    Mol Cell Neurosci 35:320-7. 2007
    ..TDP43 is a unique hNFL mRNA-binding protein that is altered in its somatotopic localization in ALS spinal motor neurons and potentially contributes to the formation of NF aggregates in ALS through alterations in NF stoichiometry...
  91. ncbi TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor
    I Fan Wang
    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    J Neurochem 105:797-806. 2008
    ....
  92. pmc TDP-43 A315T mutation in familial motor neuron disease
    Michael A Gitcho
    Alzheimer s Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, USA
    Ann Neurol 63:535-8. 2008
    ..The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration...
  93. doi TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis
    Jemeen Sreedharan
    Department of Clinical Neuroscience, King s College London, Medical Research Council MRC Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK
    Science 319:1668-72. 2008
    ..Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS...
  94. doi TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
    Edor Kabashi
    Center of Excellence in Neuromics, Centre Hospitalier de l Universite de Montreal, and Department of Medicine, University of Montreal, Montreal, Quebec H2L4MI, Canada
    Nat Genet 40:572-4. 2008
    ..These findings further corroborate that TDP-43 is involved in ALS pathogenesis...
  95. pmc TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis
    Vivianna M Van Deerlin
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Lancet Neurol 7:409-16. 2008
    ..Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1)...
  96. pmc Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
    Masato Hasegawa
    Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Kamikitazawa, Setagaya Ku, Tokyo, Japan
    Ann Neurol 64:60-70. 2008
    ..The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance of phosphorylation of TDP-43...
  97. pmc Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations
    Peter Kühnlein
    Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Feodor Lynen Strasse 23, 81377 Munich, Germany
    Arch Neurol 65:1185-9. 2008
    ..This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS...
  98. doi Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease
    Claudia Schwab
    Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada
    J Neuropathol Exp Neurol 67:1159-65. 2008
    ..Our results further add to the hypothesis that TDP-43 may be involved in the pathology of a variety of neurodegenerative disorders...
  99. doi TDP-43 accumulation is common in myopathies with rimmed vacuoles
    Benno Kusters
    Department of Pathology, Radboud University Nijmegen Medical Center, PO 9101, 6500 HB, Nijmegen, The Netherlands
    Acta Neuropathol 117:209-11. 2009
  100. pmc Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1
    Sang Hwa Kim
    Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Biol Chem 284:8083-92. 2009
    ..Our findings suggest that UBQLN is a polyubiquitin-TDP-43 cochaperone that mediates the autophagosomal delivery and/or proteasome targeting of TDP-43 aggregates...

Research Grants75

  1. TDP-43 acetylation as a pathogenic modification in ALS &related proteinopathies
    TODD JONATHAN COHEN; Fiscal Year: 2013
    ..These innovative studies will highlight TDP-43 acetylation as a critical modification linked to the progression of ALS and related TDP-43 proteinopathies. ..
  2. ALS therapies and genomics for mutant TDP-43 and TLS/FUS
    Don W Cleveland; Fiscal Year: 2010
    ..New, very high through put DNA/RNA sequencing methods will be used to identify genes whose expression is altered by the mutations, thereby identifying new targets and approaches for devising a successful therapy for ALS. ..
  3. Defining Mechanisms of TDP-43 Ubiquitination for Quality Control and Aggregation
    ERIC BERNARD DAMMER; Fiscal Year: 2012
    ....
  4. Sami Barmada; Fiscal Year: 2015
    ..Moreover, with the receipt of this Award, I will gain the opportunity to acquire the skills, knowledge, mentoring, and experience to become a successful and independent physician-scientist. ..
  5. Characterizing TDP-43 isoforms in neurodegenerative disease
    NICHOLAS THOMAS SEYFRIED; Fiscal Year: 2010
    ..The study of TDP-43 will provide deeper understanding into the pathogenesis of these diseases and potentially lead to novel therapeutic strategies. ..
  6. Phage Display Investigations of TDP-43
    RAYMOND PHILIP contact ROOS; Fiscal Year: 2010
    ..Together, this work may provide insight into why mutations of this protein cause ALS, and potentially provide a direction for treatment of sporadic and inherited ALS (as well as other neurodegenerative diseases). ..
  7. Progranulin, TAR DNA binding protein-43 and Cell Death
    Leonard Petrucelli; Fiscal Year: 2009
    ..Our hypothesis is that loss of functional PGRN leads to loss of functional TDP-43, which leads to cell death. ..
  8. Amit Berson; Fiscal Year: 2015
    ....
  9. Small Molecule Probes for TAR DNA Binding Protein 43_TDP-43
    Allen B Reitz; Fiscal Year: 2012
    ..Both diseases are now linked a protein called TAR DNA binding protein 43 (TDP-43), which aggregates in the nerve cells of patients, and we propose to generate novel molecules ..
  10. Leonard Petrucelli; Fiscal Year: 2014
    ..Our hypothesis is that loss of functional PGRN leads to loss of functional TDP-43, which leads to cell death. ..
  11. Brian C Kraemer; Fiscal Year: 2016
    ..The long term goal of this work is to develop neuroprotective strategies for neurodegenerative disorders with TPD-43 and tau protein deposits. ..
  12. Pathologically modified TDP-43 in neurodegenerative diseases
    TANIA FRANCE GENDRON; Fiscal Year: 2012
    ....
  13. In vivo modeling of TDP-43 toxicity
    JADA M LEWIS; Fiscal Year: 2011
    ..Aim 2: To identify which aspects of TDP-43 proteinopathy may be targets for therapeutic intervention. ..
  14. YOUHNA AYALA; Fiscal Year: 2015
    ..Louis. This will greatly contribute to the candidate's preparation in the field of neurodegeneration and increase the translational potential of the candidate's research. ..
  15. Scott R Barnum; Fiscal Year: 2014
    ..These studies will provide new information regarding the role of complement in ALS and potentially new therapeutic directions. ..
  16. Virginia M Lee; Fiscal Year: 2014
    ..abstract_text> ..
  17. Exploring mechanisms of TDP-43 aggregation and disaggregation
    James Shorter; Fiscal Year: 2010
    ..Realization of our objectives will empower the development of new therapies for ALS and related disorders, which are currently untreatable. ..
  18. Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies
    JAMES WAVELL AIKEN; Fiscal Year: 2011
    ....
  19. Using Drosophila as a model to understand TDP-43 function in ALS
    David B Morton; Fiscal Year: 2012
    ....
  20. Roles for TDP-43 and FUS in ALS Using Motor Neurons from Embryonic Stem Cells
    Dara Ditsworth; Fiscal Year: 2012
    ....
  21. NEIL ALAN SHNEIDER; Fiscal Year: 2015
    ....
  22. mRNA Targets for TDP-43 and FUS/TLS: Identifying Key RNA-Processing Errors in ALS
    Magdalini Polymenidou; Fiscal Year: 2012
    ..The proposed work will contribute to our understanding of the chain of events leading to this disease and to uncover targets for therapeutic interventions. ..
  23. HELAINA LEHRER; Fiscal Year: 2014
    ..Mutations in two RNA binding proteins, TAR DNA binding protein 43 (TDP43) and Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS), cause some forms of familial ..
  24. Molecular library screen for suppressors of FUS proteinopathy
    Frank P Shewmaker; Fiscal Year: 2013
    ..Our system offers a fast and inexpensive screening mechanism to find drug leads that may eventually be developed into therapeutics capable of reducing the neurodegeneration in ALS, FTLD and other disorders. ..
  25. Progranulin: Mutation and Regulation in Neurodegenerative disease
    Rosa Rademakers; Fiscal Year: 2012
    ..Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel therapeutic targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process. ..
  26. TDP-43 and FUS RNA pathways in motor neuron degeneration
    Zissimos Mourelatos; Fiscal Year: 2011
    ..We anticipate that our studies may provide important insights that will guide further investigations in therapeutic strategies to combat this lethal disease. ..
  27. Molecular and Genetic Dissection of TDP-43 Function in Neurodegeneration
    Fen Biao Gao; Fiscal Year: 2010
    ..To this end, we will use fruitfly Drosophila as our primary model system for all the proposed studies. ..
  28. Fen Biao Gao; Fiscal Year: 2016
    ..The proposed studies will significantly enhance our understanding of disease mechanisms in FTLD and may reveal novel targets for therapeutic interventions. ..
  29. Developing Diagnostic Nanobodies Against Aggregated TDP-43 Species
    Michael R Sierks; Fiscal Year: 2013
    ..Here we will develop and test similar reagents for detecting specific forms of TDP-43 that are present in FTD and ALS brain tissue. ..
  30. Defining the role of Ataxin-2 in ALS and TDP-43 proteinopathies
    Michael P Hart; Fiscal Year: 2012
    ..These experiments will expand our knowledge of the TDP-43/Ataxin-2 interaction and, more broadly, give insight into the similarities and differences of mechanisms underlying different related neurodegenerative diseases. ..
  31. Mahlon Collins; Fiscal Year: 2014
    ..Collectively, these experiments will provide new information about the role of RBM45 in normal cell function and disease. ..
  32. Benjamin L Wolozin; Fiscal Year: 2016
    ..Investigating the particular elements of the SG pathway that regulate TDP-43 inclusion formation will identify selective approaches for therapeutic intervention to delay or halt the progression of ALS. ! ..
  33. Leonard Petrucelli; Fiscal Year: 2014
    ..Overall, we believe the proposed studies examining RNA foci formation consequences will lead to a better understanding of C9FTD/ALS-related mechanisms and help to uncover promising therapeutic targets. ..
  34. Aaron D Gitler; Fiscal Year: 2015
    ..Taken together, these findings will reveal key aspects of the TDP-43/ataxin-2 interaction central to ALS, the broader role of ataxin-2 in neurodegenerative disease, and the foundation for novel therapeutic insights. ..
  35. Aaron D Gitler; Fiscal Year: 2016
    ..elegans) to explore TDP-43 disease mechanisms and validating modifier genes from our genetic screens. ..
  36. UNDERSTANDING THE ROLE OF MITOCHONDRIAL IMPORT IN AMYOTROPHIC LATERAL SCLEROSIS
    Matthew Crisp; Fiscal Year: 2013
    ..Finally, we will apply this model applies to additional forms of ALS by examining TOM protein levels in sporadic and familial TDP-43 human spinal cords. ..
  37. The mechanism linking traumatic brain injury to amyotrophic lateral sclerosis
    TERESA EVANS; Fiscal Year: 2013
    ..Interestingly, another protein, transactivation response or TAR DNA Binding Protein 43 (TDP-43), forms aggregates in both ALS and TBI which suggests that protein aggregation could be a ..
  38. Haining Zhu; Fiscal Year: 2014
    ..The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease. ..
  39. Evaluating small molecules in neuronal and yeast models of TDP-43 proteinopathy
    DANIEL TARDIFF; Fiscal Year: 2012
    ..I will study lead compounds in a mouse embryonic stem cell-derived neuronal model to help elucidate the mechanism of these two catastrophic disorders and provide lead compounds for further development. ..
  40. Craig L Bennett; Fiscal Year: 2014
    ..This underscores the importance of senataxin function in the survival of various neuronal populations. Our studies seek to determine the molecular mechanisms leading to motor neuron loss in ALS4 and further characterize the ..
  41. Transgenic Mouse Models of FUS/TLS-Mediated Amyotrophic Lateral Sclerosis
    Zuoshang Xu; Fiscal Year: 2010
    ..This project will address the urgent need to develop informative mouse models of ALS that will i) accelerate the identification of novel treatment target(s) and ii) enable the testing of new therapeutic strategies to combat ALS. ..
  42. Hiroshi Nishimune; Fiscal Year: 2016
    ....
  43. Udai B Pandey; Fiscal Year: 2016
    ..Our proposed studies are expected to provide novel insights into the molecular mechanism of FUS-related ALS that would help in developing a therapeutic interventions for ALS for which currently no cure available. ..
  44. Xu Gang Xia; Fiscal Year: 2014
    ..The resulting knockin mice will be far more physiologically relevant than any of the ALS models currently available and will be ideal for testing potential ALS therapies. ..
  45. Robert Baloh; Fiscal Year: 2014
    ..These studies will examine previously unexplored pathways of ALS pathogenesis, and identify new avenues for therapeutics development. ..
  46. Stanley H Appel; Fiscal Year: 2014
    ..These experiments will lead to the identification of the most effective human TLR2 siRNAs and treatment protocols which can be directly translated to ALS patients. ..
  47. Zuoshang Xu; Fiscal Year: 2014
    ....
  48. Hongxia Zhou; Fiscal Year: 2016
    ..Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43. ..
  49. Xu Gang Xia; Fiscal Year: 2016
    ..This proposal will determine how astrocytes contribute to the initiation and progression of motor neuron death in the presence and absence of mutant TDP-43 in astrocytes, advancing our understanding of ALS disease mechanisms. ..
  50. Identification of compounds that inhibit aggregation and toxicity of TDP-43
    Benjamin L Wolozin; Fiscal Year: 2012
    ..We will use medicinal chemistry to optimize the pharmacological properties of the two best lead compounds. We will use an iterative process, in which the lead compounds are chemically modified, tested for inclusion dispersion. ..
  51. Defining the Role of TDP-43 in Neurodegenerative Disease Pathways
    IGA NATALIA WEGORZEWSKA; Fiscal Year: 2013
    ..Additionally, we will examine whether abnormalities in RNA processing plays a fundamental role in TDP-43 related ALS, in an effort to define new targets for therapeutic intervention in ALS. ..
  52. 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. ..
  53. John E Landers; Fiscal Year: 2016
    ..In the long term, understanding the genetic causes of ALS will facilitate our understanding of all forms of ALS as well as assisting in the development of diagnostics and therapies to extend the lifespan of ALS patients. ..
  54. Generation and Characterization of Novel Drosophila Models of TDP-43 Toxicity
    Fen Biao Gao; Fiscal Year: 2013
    ..These studies will likely provide important insights into the molecular pathogenic mechanisms of several neurodegenerative diseases that involve TDP- 43 pathology. ..
  55. Yongjie Zhang; Fiscal Year: 2014
    ....
  56. MARK ALAN MCCLINTOCK; Fiscal Year: 2015
    ..nidulans pathology model. This work will not only illuminate the causes of TDP-43 based pathology, but also provide a paradigm for elucidating and understanding the pervasive transport defects of neurodegenerative diseases. ..
  57. MICHAEL ANDRE GITCHO; Fiscal Year: 2016
    ..This in vivo model potentially could lead to the development of new therapeutics targeted at slowing the progression. ..
  58. Translational Studies in VCP Inclusion Body Myopathy with Paget Disease of Bone
    Virginia Kimonis; Fiscal Year: 2009
    ..abstract_text> ..
  59. Leonard Petrucelli; Fiscal Year: 2015
    ....
  60. Guanabenz in the treatment of mutant SOD1 ALS mice
    RAYMOND PHILIP ROOS; Fiscal Year: 2013
    ....
  61. Teepu Siddique; Fiscal Year: 2016
    ..Results from this work will open paths to therapies to rescue potential dysfunctional HDL found not only in neurodegenerative disease such as ALS but also in more common cardiovascular and metabolic diseases. ..
  62. Role of High Density Lipoprotein Particles in amyotrophic lateral sclerosis
    Teepu Siddique; Fiscal Year: 2012
    ..The results from this work will open paths to therapies that seek to rescue potential dysfunctional HDL states found not only in neurodegenerative disease such as ALS but also in more common cardiovascular and metabolic diseases. ..
  63. Molecular mechanism underlying Frontotemporal Lobar Regeneration
    David Medina; Fiscal Year: 2013
    ..Successful completion of these proposed studies will represent a significant contribution to the field, and the data obtained has the potential to identify novel therapeutic targets in the fight against FTLD and TDP-43 proteinopathies. ..
  64. Deciphering RNA based mechanisms of neurodegeneration
    Daniela C Zarnescu; Fiscal Year: 2013
    ....
  65. WILLIAM TZU LUNG HU; Fiscal Year: 2016
    ..abstract_text> ..
  66. Emily Mitchell Sontag; Fiscal Year: 2016
    ..abstract_text> ..
  67. Michael Emmerson Ward; Fiscal Year: 2015
    ..abstract_text> ..
  68. Corey T McMillan; Fiscal Year: 2016
    ..The overall research aim of this proposal is to develop multimodal methods to improve in vivo diagnosis of FTLD. ..
  69. Post-transcriptional regulation of gene expression in major TDP43 diseases
    NEIL MACDONALD RENWICK; Fiscal Year: 2013
    ..This research is relevant to NIH's mission to pursue fundamental knowledge and goal to foster innovative research strategies and their applications to advance the Nation's capacity to protect and improve health. ..
  70. JADA M LEWIS; Fiscal Year: 2014
    ....
  71. Bruce L Miller; Fiscal Year: 2016
    ..Finally, we will create ideal data management approaches for neurodegenerative conditions that will be shared with other ADRCs, beginning with UC-Davis. ..
  72. Julie A Schneider; Fiscal Year: 2016
    ..Results from these proposed studies will fill an important gap in scientific knowledge and are likely to impact future studies of prevention and treatment of cognitive impairment and dementia in aging. ..
  73. Improved Transgenic Mouse Model of Alzheimer's Disease
    Karen H Ashe; Fiscal Year: 2013
    ..The development of mouse models of AD that incorporate mixed pathologies would represent a significant advancement that is likely to increase the predictive validity of pre-clinical studies in mice. ..
  74. Modeling TDP-43 Dysfunction in vivo
    Zuoshang Xu; Fiscal Year: 2009
    ..This model will test whether reduced TDP-43 function can cause neurodegeneration similar to what occurs in FTD and ALS and will be useful for studying neurodegeneration mechanism in FTD and ALS. ..
  75. Searching for Genetic Modifiers of TDP-43 Proteinopathy Using an Animal Model
    Jane Y Wu; Fiscal Year: 2011
    ..Our work will not only help elucidate pathogenic mechanisms underlying this disease but also suggest future therapeutic targets specific to TDP-43-dependent signaling pathways. ..