Reference - Detail
|Author||Liachko NF, McMillan PJ, Guthrie CR, Bird TD, Leverenz JB, Kraemer BC.|
|Title||CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration.|
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.
|MeSH||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 Frontal Lobe / pathology Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Humans Movement / physiology Mutation / genetics Neurodegenerative Diseases / drug therapy Neurodegenerative Diseases / etiology* Neurodegenerative Diseases / genetics Neurodegenerative Diseases / pathology Phosphorylation Piperidones / pharmacology Protein-Serine-Threonine Kinases / metabolism* Pyrroles / pharmacology RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Serine / metabolism TDP-43 Proteinopathies / complications TDP-43 Proteinopathies / drug therapy TDP-43 Proteinopathies / genetics TDP-43 Proteinopathies / therapy* Transfection|
|WOS Category||CLINICAL NEUROLOGY NEUROSCIENCES|
|C.elegans||tm4189 tm4127 tm3933 tm4845 tm4391 tm4516|