title: Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.
authors: 1] Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2].
authors: Hyung-Jun
authors: HJ
authors: Kim
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors: Alya R
authors: AR
authors: Raphael
authors: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors: Eva S
authors: ES
authors: LaDow
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Leeanne
authors: L
authors: McGurk
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Ross A
authors: RA
authors: Weber
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: John Q
authors: JQ
authors: Trojanowski
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Virginia M-Y
authors: VM
authors: Lee
authors: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors: Steven
authors: S
authors: Finkbeiner
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors: Aaron D
authors: AD
authors: Gitler
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Nancy M
authors: NM
authors: Bonini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000067528:Ataxins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D063990:Gene Ontology; D057166:High-Throughput Screening Assays; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008164:Luminescent Proteins; D009046:Motor Neurons / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D034622:RNA Interference; D012160:Retina / Q000378:metabolism / Q000648:ultrastructure; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D054852:Small Molecule Libraries; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D000225:Adenine; D000067528:Ataxins; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D039102:Poly(A)-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D000097573:Red Fluorescent Protein; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine; C083327:PUB1 protein, S cerevisiae