Kinetic barriers to α-synuclein protofilament formation and conversion into mature fibrils

Oligomeric and protofibrillar aggregates that are populated along the pathway of amyloid fibril formation appear generally to be more toxic than the mature fibrillar state. In particular, α-synuclein, the protein associated with Parkinson's disease, forms kinetically trapped protofibrils in the...

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Published inChemical communications (Cambridge, England) Vol. 54; no. 56; pp. 7854 - 7857
Main Authors Brown, James W P, Meisl, Georg, Knowles, Tuomas P J, Buell, Alexander K, Dobson, Christopher M, Galvagnion, Céline
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 10.07.2018
Subjects
Conversion
Molecular structure
Parkinson's disease
Proteins
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Summary:Oligomeric and protofibrillar aggregates that are populated along the pathway of amyloid fibril formation appear generally to be more toxic than the mature fibrillar state. In particular, α-synuclein, the protein associated with Parkinson's disease, forms kinetically trapped protofibrils in the presence of lipid vesicles. Here, we show that lipid-induced α-synuclein protofibrils can convert rapidly to mature fibrils at higher temperatures. Furthermore, we find that β-synuclein, generally considered less aggregation prone than α-synuclein, forms protofibrils at higher temperatures. These findings highlight the importance of energy barriers in controlling the de novo formation and conversion of amyloid fibrils.
ISSN:1359-7345
1364-548X
DOI:10.1039/c8cc03002b