Laurine E, Grégoire C, Fändrich M, Engemann S, Marchal S, Thion L, Mohr M, Monsarrat B, Michel B, Dobson CM, Wanker E, Erard M, Verdier JM. Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease. J Biol Chem. 2003 Dec 19;278(51):51770-8. PubMed.
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UNC Chapel Hill
Penn State University
Laurine et al. study lithostathine, a protein that has been shown to be overexpressed in the preclinical stages of Alzheimer's disease. Upon autocatalytic cleavage, lithostathine forms fibrils that have been found in the lesions of Alzheimer's disease. The authors examined the characteristics of fibrils formed from lithostathine. They conclude that if the lithostathine fibrils are in fact amyloid structures, they would represent a new class of amyloid fibrils, one that does not share many of the characteristics of typical amyloid fibrils. Specifically, lithostathine fibrils do not bind Congo red and have a different infrared spectrum. The authors instead claim that lithostathine fibrils are a disease-associated, abnormal protein fibril that is not amyloid in nature.
Laurine et al. also assessed the role of autocatalytic cleavage on the dimerization and aggregation of lithostathine. They found that as soon as lithostathine is cleaved, it begins to assemble into multimers, potentially through domain swapping, as lithostathine is a member of a protein family that is predisposed to undergo domain swapping. The authors located a cluster of six conserved tryptophans, positioned along a surface loop, that could act as a mobile structural element which can be swapped between adjacent lithostathine molecules and therefore enable the formation of fibril bundles.
One interesting characteristic of lithostathine fibrils is the fact that they are dissociated by [6,6']dibenzothiazolyl-2,2'-diamine (PGL-034), a compound that has been previously shown to disrupt the aggregation events associated with Huntington's disease. The authors claim that PGL-034 is capable of binding to the domain-swapping region, disrupting intermolecular interactions between lithostathine molecules. They also claim that PGL-034 could therefore be a potential therapeutic agent against lithostathine fibril formation.
Lastly, Laurine et al. show that lithostathine deposits are present in brain tissue taken from patients with Creutzfeldt-Jakob disease. This suggests that different forms of protein deposits could coexist in the same neurodegenerative disease.
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