Abstract
The biological function of α-Synuclein has been related to binding to lipids and membranes but these interactions can also mediate α-Synuclein aggregation, which is associated to Parkinson’s disease and other neuropathologies. In brain tissue α-Synuclein is constitutively N-acetylated, a modification that plays an important role in its conformational propensity, lipid and membrane binding, and aggregation propensity. We studied the interactions of the lipid-mimetic SDS with N-acetylated and non-acetylated α-Synuclein, as well as their early-onset Parkinson’s disease variants A30P, E46K and A53T. At low SDS/protein ratios α-Synuclein forms oligomeric complexes with SDS micelles with relatively low α-helical structure. These micellar oligomers can efficiently nucleate aggregation of monomeric α-Synuclein, with successive formation of oligomers, protofibrils, curly fibrils and mature amyloid fibrils. N-acetylation reduces considerably the rate of aggregation of WT α-Synuclein. However, in presence of any of the early-onset Parkinson’s disease mutations the protective effect of N-acetylation against micelle-induced aggregation becomes impaired. At higher SDS/protein ratios, N-acetylation favors another conformational transition, in which a second type of α-helix-rich, non-aggregating oligomers become stabilized. Once again, the Parkinson’s disease mutations disconnect the influence of N-acetylation in promoting this transition. These results suggest a cooperative link between the N-terminus and the region of the mutations that may be important for α-Synuclein function.
Highlights
Parkinson’s disease (PD) is the most common neuronal motor system disorder affecting more than 1% of the population aged over 65 [1]
We chose this low ionic strength buffer in order to attain a relatively wide sub-critical micellar concentration (CMC) sodium dodecyl sulfate (SDS) concentration range, since previous studies have shown that binding of helical aggregates of proteins. αSynuclein (aS) to bulk SDS micelles protects it from aggregation [36]
We explored the influence of the early-onset PD mutations A30P, E46K and A53T, on the conformational changes and interactions of aS and acetylated aS (Ac-aS) induced by SDS by CD and dynamic light scattering (DLS) measurements
Summary
Parkinson’s disease (PD) is the most common neuronal motor system disorder affecting more than 1% of the population aged over 65 [1].
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