Role of Parkinson’s Disease-Linked Mutations and N-Terminal Acetylation on the Oligomerization of α-Synuclein Induced by 3,4-Dihydroxyphenylacetaldehyde

Abstract

Identifying the mechanisms by which the presynaptic protein α-synuclein (aSyn) is associated to neurodegeneration of dopamine neurons is a major priority in the Parkinson's disease (PD) field. Studies indicate that DOPAL (3,4-dihydroxyphenylacetaldehyde), an aldehyde generated from the enzymatic oxidation of dopamine, may convert aSyn monomer into a neurotoxin via formation of covalently stabilized toxic oligomers. Herein we investigated the role of N-terminal acetylation and familial aSyn mutations (A30P, A53T, E46K, G51D and H50Q) on DOPAL-induced oligomerization of the protein. Our results indicate that wild-type (WT) N-terminally acetylated-aSyn (Ac-aSyn) is less prone to form oligomers upon incubation with DOPAL than the non-Nterminally acetylated protein. On the other hand, familial mutants from Ac-aSyn, particularly A53T, E46K and H50Q increased the formation of DOPAL-derived aSyn oligomers, especially large oligomers. Binding of aSyn to synaptic-like small unilamellar vesicles (SUVs) protected distinctively aSyn variants against the effects of DOPAL. While N-terminal acetylation increased the protective action of against DOPAL-induced aSyn oligomerization, A53T, A30P and H50Q mutations in Ac-aSyn had an opposite effect. It means that PD-linked mutations may not only perturb the affinity of aSyn for membranes but also influence the formation of DOPAL-mediated oligomers. Overall, our findings provide important evidences for the existence of a connection between familial mutations of aSyn, and their distinct affinity to lipid membranes, and the formation of potentially toxic oligomers of the protein mediated by DOPAL.

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

“…For mutated versions of a-Syn that are associated with early-onset PD (A30P, E46K, and A53T), the anti-aggregation effect of Nt acetylation becomes impaired, suggesting a cooperative link between the regions of these mutations and the N terminus (Ruzafa et al, 2017). PD specifically affects dopaminergic neurons, and a neurotoxic effect on a-Syn caused by DOPAL (3,4-dihydroxyphenylacetaldehyde), a biproduct in the synthesis of dopamine, has been investigated by Lima et al (2018), among others. Very recently, they found that wild-type Nt-acetylated a-Syn is less prone to form oligomers in the presence of DOPAL than non-Nt-acetylated a-Syn, whereas the opposite was found for inherited mutations of a-Syn (A53T, E46K, and H50Q) (Lima et al, 2018).…”

“…PD specifically affects dopaminergic neurons, and a neurotoxic effect on a-Syn caused by DOPAL (3,4-dihydroxyphenylacetaldehyde), a biproduct in the synthesis of dopamine, has been investigated by Lima et al (2018), among others. Very recently, they found that wild-type Nt-acetylated a-Syn is less prone to form oligomers in the presence of DOPAL than non-Nt-acetylated a-Syn, whereas the opposite was found for inherited mutations of a-Syn (A53T, E46K, and H50Q) (Lima et al, 2018).…”

Effects of alpha‐synuclein post‐translational modifications on metal binding

“…Although AcAS was capable of forming oligomers in the presence of DOPAL, the extent of oligomerization was significantly reduced. However, AcAS carrying the familial mutations A53T, E46K, or H50Q formed larger oligomers than WT AS (Lima et al ).…”

“…In a recent study, the effect of familial mutations on DOPAL induced oligomerization of AS was investigated (Lima et al ). 3,4‐dihydroxyphenylacetaldehyde (DOPAL), an aldehyde generated from the enzymatic oxidation of dopamine, causes the formation of AS oligomers.…”

The Roles of Post-translational Modifications on α-Synuclein in the Pathogenesis of Parkinson’s Diseases

“…3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a catabolite generated from dopamine by monoamine oxidase (Burke et al, 2003; Goldstein et al, 2011). It has been shown that DOPAL can cause α-synuclein oligomerization in vitro and in cell models (Burke et al, 2008; Lima et al, 2018). Plotegher et al (2017) showed that this kind of α-synuclein-DOPAL oligomers can permeabilize cholesterol-containing lipid membranes mimicking SVs in vitro , which suggests that the synergistic effect of α-synuclein and DOPAL accumulation in DA neurons may lead to the formation of oligomers, negatively impacting the structure and function of SVs.…”