Inhibition of amyloid fibrillogenesis and toxicity by a peptide chaperone.
Aggregation of proteins in tissues is associated with several diseases, including Alzheimer's disease. It is characterized by the accumulation of amyloid beta peptide (Abeta) in the extracellular spaces of the brain cells, resulting in neuronal death and other pathological changes. alpha-Crystallin, a small heat-shock protein in lens, and a peptide chaperone having the functional site sequence DFVIFLDVKHFSPEDLTVK of alphaA-crystallin may inhibit Abeta fibrillogenesis and toxicity. The peptide chaperone (mini-alphaA-crystallin), having an Abeta interacting domain and a complex solubilizing domain, was shown in previous studies to prevent aggregation of several proteins under denaturing conditions. In this in vitro study, using transmission electron microscopy and thioflavin T binding assay, we show that mini-alphaA-crystallin arrests the fibril formation of Abeta peptides. Mini-alphaA-crystallin also suppresses the toxic action of Abeta on rat pheochromocytoma (PC 12) cells. The wide chaperoning capability of the peptide and its ability to inhibit amyloid fibril formation and suppress toxicity suggest that mini-alphaA-crystallin may serve as a universal chaperone in controlling diseases of protein aggregation, including Alzheimer's disease.
Santhoshkumar
Puttur
P
Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA.
Sharma
Krishna K
KK
D000544:Alzheimer Disease / Q000517:prevention & control*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000648:ultrastructure; D000818:Animals; D001216:Asparagine / Q000378:metabolism; D052160:Benzothiazoles; D002470:Cell Survival / Q000187:drug effects; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry / Q000633:toxicity*; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D018675:Toxicity Tests; D038201:alpha-Crystallins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D018832:Molecular Chaperones; D013844:Thiazoles; D038201:alpha-Crystallins; C009462:thioflavin T; D001216:Asparagine