A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity
TDP-43 is an RNA binding protein found to accumulate in the cytoplasm of brain and spinal cord from patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nuclear TDP-43 protein regulates transcription through several mechanisms, and under stressed c...
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Published in | Journal of biomolecular screening Vol. 19; no. 1; pp. 44 - 56 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.01.2014
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Abstract | TDP-43 is an RNA binding protein found to accumulate in the cytoplasm of brain and spinal cord from patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nuclear TDP-43 protein regulates transcription through several mechanisms, and under stressed conditions, it forms cytoplasmic aggregates that co-localize with stress granule (SG) proteins in cell culture. These granules are also found in the brain and spinal cord of patients affected with ALS and FTLD. The mechanism through which TDP-43 might contribute to neurodegenerative diseases is poorly understood. To investigate the pathophysiology of TDP-43 aggregation and to isolate potential therapeutic targets, we screened a chemical library of 75,000 compounds using high-content analysis with PC12 cells that inducibly express human TDP-43 tagged with green fluorescent protein (GFP). The screen identified 16 compounds that dose-dependently decreased the TDP-43 inclusions without significant cellular toxicity or changes in total TDP-43 expression levels. To validate the effect, we tested compounds by Western blot analysis and in a Caenorhabditis elegans model that replicates some of the relevant disease phenotypes. The hits from this assay will be useful for elucidating regulation of TDP-43, stress granule response, and possible ALS therapeutics. |
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AbstractList | TDP-43 is an RNA binding protein found to accumulate in the cytoplasm of brain and spinal cord from patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nuclear TDP-43 protein regulates transcription through several mechanisms, and under stressed conditions, it forms cytoplasmic aggregates that co-localize with stress granule (SG) proteins in cell culture. These granules are also found in the brain and spinal cord of patients affected with ALS and FTLD. The mechanism through which TDP-43 might contribute to neurodegenerative diseases is poorly understood. To investigate the pathophysiology of TDP-43 aggregation and to isolate potential therapeutic targets, we screened a chemical library of 75,000 compounds using high-content analysis with PC12 cells that inducibly express human TDP-43 tagged with green fluorescent protein (GFP). The screen identified 16 compounds that dose-dependently decreased the TDP-43 inclusions without significant cellular toxicity or changes in total TDP-43 expression levels. To validate the effect, we tested compounds by Western blot analysis and in a Caenorhabditis elegans model that replicates some of the relevant disease phenotypes. The hits from this assay will be useful for elucidating regulation of TDP-43, stress granule response, and possible ALS therapeutics. |
Author | Zauur, Nava Lee, Peter Ebata, Atsushi Feiler, Marisa S Boyd, Justin D Wolozin, Benjamin Liu, Min Concannon, John Glicksman, Marcie A |
Author_xml | – sequence: 1 givenname: Justin D surname: Boyd fullname: Boyd, Justin D organization: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA – sequence: 2 givenname: Peter surname: Lee fullname: Lee, Peter organization: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA – sequence: 3 givenname: Marisa S surname: Feiler fullname: Feiler, Marisa S organization: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA – sequence: 4 givenname: Nava surname: Zauur fullname: Zauur, Nava organization: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA – sequence: 5 givenname: Min surname: Liu fullname: Liu, Min organization: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA – sequence: 6 givenname: John surname: Concannon fullname: Concannon, John organization: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA – sequence: 7 givenname: Atsushi surname: Ebata fullname: Ebata, Atsushi organization: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA – sequence: 8 givenname: Benjamin surname: Wolozin fullname: Wolozin, Benjamin organization: Department of Neurology, Boston University School of Medicine, Boston, MA – sequence: 9 givenname: Marcie A surname: Glicksman fullname: Glicksman, Marcie A organization: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24019256$$D View this record in MEDLINE/PubMed |
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Snippet | TDP-43 is an RNA binding protein found to accumulate in the cytoplasm of brain and spinal cord from patients affected with amyotrophic lateral sclerosis (ALS)... |
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SubjectTerms | Animals Animals, Genetically Modified Arsenites - pharmacology Caenorhabditis elegans Cell Line DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Discovery - methods Drug Evaluation, Preclinical - methods Gene Expression Genes, Reporter High-Throughput Screening Assays Humans Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - genetics Neurodegenerative Diseases - metabolism Neuroprotective Agents - pharmacology Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Small Molecule Libraries Sodium Compounds - pharmacology Stress, Physiological - drug effects |
Title | A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity |
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