Document Detail


CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration.
MedLine Citation:
PMID:  23424178     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
INTERPRETATION: Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis.
Authors:
Nicole F Liachko; Pamela J McMillan; Chris R Guthrie; Thomas D Bird; James B Leverenz; Brian C Kraemer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-07-08
Journal Detail:
Title:  Annals of neurology     Volume:  74     ISSN:  1531-8249     ISO Abbreviation:  Ann. Neurol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-09-16     Completed Date:  2013-11-07     Revised Date:  2014-07-09    
Medline Journal Info:
Nlm Unique ID:  7707449     Medline TA:  Ann Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39-52     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Neurological Association.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Caenorhabditis elegans Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Transformed
DNA-Binding Proteins / metabolism*
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Frontal Lobe / metabolism,  pathology
Gene Expression Regulation / drug effects,  genetics
Humans
Movement / physiology
Mutation / genetics
Neurodegenerative Diseases / drug therapy,  etiology*,  genetics,  pathology
Phosphorylation
Piperidones / pharmacology
Protein-Serine-Threonine Kinases / metabolism*
Pyrroles / pharmacology
RNA, Small Interfering / genetics,  metabolism
Serine / metabolism
TDP-43 Proteinopathies / complications,  drug therapy,  genetics,  therapy*
Transfection
Grant Support
ID/Acronym/Agency:
AG 000057-31/AG/NIA NIH HHS; P50 AG005136/AG/NIA NIH HHS; P50AG005136-27/AG/NIA NIH HHS; P50NS2062684-02/NS/NINDS NIH HHS; R01 NS064131/NS/NINDS NIH HHS; R01NS064131/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Caenorhabditis elegans Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/PHA 767491; 0/Piperidones; 0/Pyrroles; 0/RNA, Small Interfering; 0/protein TDP-43; 452VLY9402/Serine; EC 2.7.1.-/CDC7 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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