title: CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration.
abstract: OBJECTIVE
  Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. 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.
  
  
  METHODS
  To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic Caenorhabditis elegans.
  
  
  RESULTS
  We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathology found in frontal cortex. Furthermore, PHA767491, a small molecule inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43-transgenic animals.
  
  
  CONCLUSIONS
  Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis.
authors: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA.
authors: Nicole F
authors: NF
authors: Liachko
authors: Pamela J
authors: PJ
authors: McMillan
authors: Chris R
authors: CR
authors: Guthrie
authors: Thomas D
authors: TD
authors: Bird
authors: James B
authors: JB
authors: Leverenz
authors: Brian C
authors: BC
authors: Kraemer
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009068:Movement / Q000502:physiology; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D010881:Piperidones / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D014162:Transfection
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C531237:PHA 767491; D010881:Piperidones; D011758:Pyrroles; D034741:RNA, Small Interfering; D012694:Serine; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases