C-terminal truncation of α-synuclein promotes amyloid fibril amplification at physiological pH. Issue 25 (5th June 2018)

• Record Type: Journal Article
• Authors: van der Wateren, Ingrid M.; Knowles, Tuomas P. J.; Buell, Alexander K.; Dobson, Christopher M.; Galvagnion, Céline
• Is Part Of: Chemical science. Volume 9:Issue 25(2018)
• Page Start: 5506
• Page End: 5516
• Publication Date: 2018-06-05
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc01109e
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : C-terminal truncations shift the pH range at which α-synuclein secondary nucleation occurs from acidic to neutral values. Abstract : Parkinson's disease is one of the major neurodegenerative disorders affecting the ageing populations of the modern world. One of the hallmarks of this disease is the deposition of aggregates, mainly of the small pre-synaptic protein α-synuclein (AS), in the brains of patients. Several very significantly modified forms of AS have been found in these deposits including those resulting from truncations of the protein at its C-terminus. Here, we report how two physiologically relevant C-terminal truncations of AS, AS(1-119) and AS(1-103), where either half or virtually all of the C-terminal domain, respectively, has been truncated, affect the mechanism of AS aggregation and the properties of the fibrils formed. In particular, we have found that the deletion of these C-terminal residues induces a shift of the pH region where autocatalytic secondary processes dominate the kinetics of AS aggregation towards higher pH values, from AS wild-type (pH 3.6–5.6) to AS(1-119) (pH 4.2–7.0) and AS(1-103) (pH 5.6–8.0). In addition, we found that both truncated variants formed protofibrils in the presence of lipid vesicles, but only those formed by AS(1-103) had the capacity to convert readily into mature fibrils. These results suggest that electrostatics play an important role in secondary nucleation, a key factor in aggregate proliferation, and in the conversion of AS fibrils from protofibrils to mature fibrils. In particular, our results demonstrate that sequence truncations of AS can shift the pH range where autocatalytic proliferation of fibrils is possible into the neutral, physiological regime, thus providing an explanation of the increased propensity of the C-truncated variants to aggregate in vivo .