Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration.
Although Abl functions in mature neurons, work to date has not addressed Abl's role on Cdk5 in neurodegeneration. We found that beta-amyloid (Abeta42) initiated Abl kinase activity and that blockade of Abl kinase rescued both Drosophila and mammalian neuronal cells from cell death. We also found activated Abl kinase to be necessary for the binding, activation, and translocalization of Cdk5 in Drosophila neuronal cells. Conversion of p35 into p25 was not observed in Abeta42-triggered Drosophila neurodegeneration, suggesting that Cdk5 activation and protein translocalization can be p25-independent. Our genetic studies also showed that abl mutations repressed Abeta42-induced Cdk5 activity and neurodegeneration in Drosophila eyes. Although Abeta42 induced conversion of p35 to p25 in mammalian cells, it did not sufficiently induce Cdk5 activation when c-Abl kinase activity was suppressed. Therefore, we propose that Abl and p35/p25 cooperate in promoting Cdk5-pY15, which deregulates Cdk5 activity and subcellular localization in Abeta42-triggered neurodegeneration.
Lin
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Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
Lin
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Juang
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D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000201:enzymology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; C075222:amyloid beta-protein (1-42); C089495:neuronal Cdk5 activator (p25-p35); D016315:Proto-Oncogene Proteins c-abl; D051360:Cyclin-Dependent Kinase 5