The role of protein aggregates in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease and ALS, may be as much about their mere presence as their specific form or identity. Recent studies led by Ken Hun Mok of Trinity College Dublin in Ireland investigated how the oligomeric versus mature amyloid fibrils of a non-disease protein could be toxic and lead to cognitive deficits. The scientists, including first author Nial Harte, developed a specialized assay using Hen Egg White Lysozyme (HEWL) protein that was manipulated to take on oligomeric vs. amyloid fibril forms. The results, published in the November 20 Journal of Biological Chemistry, showed that the prefibrillar oligomers and mature fibril forms were all cytotoxic to rat pheochromocytoma (PC12) cultured cells, and promoted cell death through disparate mechanisms. However, when tested in vivo, only the oligomers, the smallest of the forms, inhibited hippocampal long term potentiation (LTP). The results taken together suggest that aggregates of varying sizes all contribute to the development of neurodegenerative diseases through distinct mechanisms, from inducing neuron loss through impairing brain function via LTP inhibition. Understanding these nuances could aid in the development of therapies that target diverse protein aggregates, including those characteristic of ALS, such as TDP-43 (see June 2011 news, Sept 2014 news).
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Harte NP, Klyubin I, McCarthy EK, Min S, Garrahy SA, Xie Y, Davey GP, Boland JJ, Rowan MJ, Mok KH. Amyloid Oligomers and Mature Fibrils Prepared from an Innocuous Protein Cause Diverging Cellular Death Mechanisms. J. Biol. Chem. 2015. Nov 20;290(47):28343-52. [Pubmed].