Interaction of intracellular beta amyloid peptide with chaperone proteins.
Expression of the human beta amyloid peptide (A beta) in transgenic Caenorhabditis elegans animals can lead to the formation of intracellular immunoreactive deposits as well as the formation of intracellular amyloid. We have used this model to identify proteins that interact with intracellular A beta in vivo. Mass spectrometry analysis of proteins that specifically coimmunoprecipitate with A beta has identified six likely chaperone proteins: two members of the HSP70 family, three alpha B-crystallin-related small heat shock proteins (HSP-16s), and a putative ortholog of a mammalian small glutamine-rich tetratricopeptide repeat-containing protein proposed to regulate HSP70 function. Quantitative reverse transcription-PCR analysis shows that the small heat shock proteins are also transcriptionally induced by A beta expression. Immunohistochemistry demonstrates that HSP-16 protein closely colocalizes with intracellular A beta in this model. Transgenic animals expressing a nonaggregating A beta variant, a single-chain A beta dimer, show an altered pattern of coimmunoprecipitating proteins and an altered cellular distribution of HSP-16. Double-stranded RNA inhibition of R05F9.10, the putative C. elegans ortholog of the human small glutamine-rich tetratricopeptide-repeat-containing protein (SGT), results in suppression of toxicity associated with A beta expression. These results suggest that chaperone function can play a role in modulating intracellular A beta metabolism and toxicity.
Fonte
Virginia
V
Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA.
Kapulkin
Wadim Jan
WJ
Kapulkin
Vadim
V
Taft
Andrew
A
Fluet
Amy
A
Friedman
David
D
Link
Christopher D
CD
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42)