Researchers hope to speed up the diagnosis of amyloid diseases, such as Parkinson's and arthritis, by detecting intermediate structures that are toxic.
From the paper; Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers by Hopping et al.
Arthritic knee joint. Image CCBY 2.0 Sethoscope.
The build up of very thin fibres called amyloid fibrils is known to lead to more than 40 different human diseases, including Parkinson’s disease and rheumatoid arthritis. These diseases involve soluble proteins or peptides joining other proteins or peptides to form the fibrils, which are not soluble. However, the damage is done by the time the fibrils form because soluble intermediate structures formed by the proteins and peptides are toxic. The development of methods that can detect these toxic intermediate structures could lead to earlier interventions before significant damage.
Amyloid fibrils are known to have a beta-sheet structure that is found in many protein systems. In 2004, based on computer simulations, researchers predicted that proteins and peptides that go on to form amyloid fibrils would pass through a related but less stable structure called an alpha-sheet, and that this structure would be toxic. Now Hopping et al., including some of the researchers involved in the 2004 work, have confirmed that the alpha-sheet structure is indeed involved in the formation of amyloid fibrils.
To do this Hopping et al. designed peptides with alpha-sheet structures that could bind to the alpha-sheet structures predicted by their simulations. When these complementary designed peptides were added to a solution of peptide that causes Alzheimer’s Disease, or a protein that causes systemic amyloid disease, the designed peptides bound the toxic peptides or proteins and prevented the formation of fibrils.
The results of Hopping et al. suggest that designed alpha-sheet compounds might be able to capture peptides and proteins that are implicated in a wide variety of amyloid diseases, independent of their composition and native structure, by targeting the intermediate alpha-sheet structure. Future challenges include showing that most proteins and peptides pass through this intermediate structure as they form fibrils, and improving the sensitivity of the binding in the hope of developing diagnostics for amyloid diseases.
