Suppression ofin Vivoβ-Amyloid Peptide Toxicity by Overexpression of the HSP-16.2 Small Chaperone Protein

Virginia Fonte, D. Randal Kipp, John Yerg, David Merin, Margaret Forrestal, Eileen Wagner, Christine M. Roberts, Christopher D. Link
2007 Journal of Biological Chemistry  
Expression of the human ␤-amyloid peptide (A␤) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 proteins, a family of small heat shockinducible proteins homologous to vertebrate ␣B crystallin. These proteins also co-localize and co-immunoprecipitate with A␤ in this model (Fonte, V., Kapulkin, V., Taft , A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439 -9444). To investigate the molecular basis and
more » ... al function of this interaction between HSP-16 and A␤, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses A␤ toxicity. Wild type A␤-(1-42), but not A␤ single chain dimer, was observed to become sequestered in HSP-16.2containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and A␤ in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of A␤ peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to A␤ in vitro, with a preferential affinity for oligomeric A␤ species. This interaction between A␤ and HSP-16.2 also influences the formation of A␤ oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce A␤ toxicity by interacting directly with the A␤ peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species. . 2 The abbreviations used are: A␤, ␤-amyloid peptide; AD, Alzheimer disease; ER, endoplasmic reticulum; BSA, bovine serum albumin; WT, wild type; PBS, phosphate-buffered saline; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; IBM, inclusion body myositis; sHSP, small heat shock protein; GFP, green fluorescent protein.
doi:10.1074/jbc.m703339200 pmid:17993648 fatcat:arwps66cizgm7lzgqyb3p26jbu