Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein

• Published in: FEBS letters Vol. 576; no. 3; pp. 363 - 368
• Main Authors: Choi, Woong, Zibaee, Shahin, Jakes, Ross, Serpell, Louise C., Davletov, Bazbek, Anthony Crowther, R., Goedert, Michel
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 22.10.2004
• Subjects: alpha-Synuclein; Amino Acid Substitution; Animals; Binding Sites; Dementia with Lewy bodies; Filament assembly; Humans; Kinetics; L Cells (Cell Line); Lewy Body Disease - genetics; Lipid binding; Liposomes; Mice; Mutagenesis, Site-Directed; Mutation, Missense; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - ultrastructure; Parkinson Disease - genetics; Parkinson's disease; Phospholipids - metabolism; Synucleins; α-Synuclein; α-Synuclein; Filament assembly; Parkinson's disease; Lipid binding; Dementia with Lewy bodies
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2004.09.038

Missense mutations (A30P and A53T) in α-synuclein and the overproduction of the wild-type protein cause familial forms of Parkinson's disease and dementia with Lewy bodies. α-Synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define these diseases at a neuropathological level. Recently, a third missense mutation (E46K) in α-synuclein was described in an inherited form of dementia with Lewy bodies. Here, we have investigated the functional effects of this novel mutation on phospholipid binding and filament assembly of α-synuclein. When compared to the wild-type protein, the E46K mutation caused a significantly increased ability of α-synuclein to bind to negatively charged liposomes, unlike the previously described mutations. The E46K mutation increased the rate of filament assembly to the same extent as the A53T mutation. Filaments formed from E46K α-synuclein often had a twisted morphology with a cross-over spacing of 43 nm. The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in α-synuclein.