Dopamine quinones interact with α-synuclein to form unstructured adducts

Dopamine cannot promote oligomerization of unoxidized <i>α</i>-synuclein

“…These results suggest that an association with DA could be a trigger of oligomeri- zation, and some oxidations of α-synuclein are required to proceed with oligomerization. The observations of oligomers comprising α-synuclein with four oxidized Met [9][10][11] coincide with the present results of size exclusion chromatography. In γ-synuclein, which is another member of the synuclein family, M38 and Y39 can be easily oxidized and γ-synuclein can form annular oligomers that accumulate in cells [20].…”

“…It is localized at presynaptic terminals in close proximity to synaptic vesicles [1,[4][5][6], as well as in the neuronal nuclei [7]. Recently, interactions between α-synuclein and dopamine (DA) have been vigorously studied [8][9][10][11][12]. These studies suggest that distinctly reactive intermediates of α-synuclein interacting with DA induce its oligomerization [10].…”

Oligomerization and Membrane-binding Properties of Covalent Adducts Formed by the Interaction of α-Synuclein with the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL)

“…DOPAL/DPQ Modify Lysine Residues in aS-Although various reports have indicated the formation of covalent adducts between dopamine or dopamine oxidation products and aS (47,48), the precise nature of such modifications and the sites on aS where they occur have remained unclear. We developed a protocol for modifying aS with purified DOPAL and have shown that this modification leads to the formation of small aS oligomers in a manner that depends on DOPAL oxidation to DPQ.…”

Dopamine‐induced α‐synuclein oligomers show self‐ and cross‐propagation properties

“…Given that purified DSOs seem to be off-pathway oligomeric species by virtue of failing to form fibrils even after extended periods of time, it is likely that cross-linking with DA traps aS in its extended, random coil conformation as reported previously. 25,26 It is unlikely that random coil aggregates in the absence of cross-linking would represent the deep kinetic minima necessary to prevent fibril formation. However, oligomerization of intrinsically disordered proteins without gain in structure by a heterotypic, liquid-liquid demixing like mechanism has been proposed for polyglutamine proteins involved in Huntington's disease, 27,28 and a gain in oligomerization state without a corresponding transition from disorder to order is emerging to be a realistic mechanism among intrinsically disordered proteins.…”