Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein.
Intracellular α-synuclein deposits, known as Lewy bodies, have been linked to a range of neurodegenerative disorders, including Parkinson's disease. α-Synuclein binds to synthetic and biological lipids, and this interaction has been shown to play a crucial role for both α-synuclein's native function, including synaptic plasticity, and the initiation of its aggregation. Here, we describe the interplay between the lipid properties and the lipid binding and aggregation propensity of α-synuclein. In particular, we have observed that the binding of α-synuclein to model membranes is much stronger when the latter is in the fluid rather than the gel phase, and that this binding induces a segregation of the lipids into protein-poor and protein-rich populations. In addition, α-synuclein was found to aggregate at detectable rates only when interacting with membranes composed of the most soluble lipids investigated here. Overall, our results show that the chemical properties of lipids determine whether or not the lipids can trigger the aggregation of α-synuclein, thus affecting the balance between functional and aberrant behavior of the protein.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Céline
0000-0001-9753-3310
C
Galvagnion
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
James W P
JW
Brown
Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom;
Myriam M
MM
Ouberai
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Patrick
P
Flagmeier
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Michele
M
Vendruscolo
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Alexander K
AK
Buell
Division of Physical Chemistry, Chemistry Department, Lund University, 22100 Lund, Sweden.
Emma
E
Sparr
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; cmd44@cam.ac.uk.
Christopher M
CM
Dobson
D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D008051:Lipid Bilayers; D051844:alpha-Synuclein
Parkinson’s disease; lipid-induced aggregation; phase diagram; α-synuclein