Inhibition of α‐synuclein fibrillization by dopamine analogs via reaction with the amino groups of α‐synuclein

Abstract

Parkinson's disease (PD) is a common movement disorder characterized by degeneration of dopaminergic neurons and deposition of fibrillar Lewy bodies comprising primarily a-synuclein (a-Syn) in the substantia nigra [1][2][3][4]. A growing body of evidence strongly supports the theory that formation of a-Syn fibrils and dopamine (DA) metabolism are closely associated with the pathogenesis of this fatal disease [5][6][7]. These findings imply an intrinsic link between the presynaptic a-Syn protein and the DA molecule [8], a synaptic neurotransmitter that functions in signal transmission. Recent research has focused on oxidative stress in brain, DA metabolism and dysfunction of a-Syn in synapses, in an attempt to elucidate an overview linking these important biological processes. Conway et al. [9] reported that DA stabilized the a-Syn protofibrils by forming a DA-a-Syn adduct. They proposed that DA could react with the phenol Fibrillization of a-synuclein (a-Syn) is closely associated with the formation of Lewy bodies in neurons and dopamine (DA) is a potent inhibitor for the process, which is implicated in the causative pathogenesis of Parkinson's disease (PD). To elucidate any molecular mechanism that may have biological relevance, we tested the inhibitory abilities of DA and several analogs including chemically synthetic and natural polyphenols in vitro. The MS and NMR characterizations strongly demonstrate that DA and its analogs inhibit a-Syn fibrillization by a mechanism where the oxidation products (quinones) of DA analogs react with the amino groups of a-Syn chain, generating a-Syn-quinone adducts. It is likely that the amino groups of a-Syn undergo nucleophilic attack on the quinone moiety of DA analogs to form imino bonds. The covalently cross-linked a-Syn adducts by DA are primarily large molecular mass oligomers, while those by catechol and p-benzoquinone (or hydroquinone) are largely monomers or dimers. The DA quinoprotein retains the same cytotoxicity as the intact a-Syn, suggesting that the oligomeric intermediates are the major elements that are toxic to the neuronal cells. This finding implies that the reaction of a-Syn with DA is relevant to the selective dopaminergic loss in PD.Abbreviations Ab, amyloid b-protein; AFM, atomic force microscopy; CA, catechol; DA, dopamine; DAQ, dopamine-quinone; EGCG, (-)-epigallocatechin gallate; GAV, a peptide motif with a homologous sequence of VGGAVVAGV; HQ, hydroquinone; HSQC, heteronuclear single quantum coherence; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC, nonamyloid component; NBT, nitroblue tetrazolium chloride; pNP, p-nitrophenol; PrP, prion protein; pXG, p-xylylene glycol; Q, p-benzoquinone; a-Syn, human a-synuclein; ThT, thioflavin T.

The Anti-Parkinsonian Drug Selegiline Delays the Nucleation Phase of α-Synuclein Aggregation Leading to the Formation of Nontoxic Species

“…Although not presented here, it has been shown previously that protofibrils formed in the presence of DA are toxic to cells in culture. 45,51 As seen in Fig. 6d (inverted triangles), the toxicity of the aggregate species formed in the presence of DA Sel presented a profile similar to that displayed by the control sample (filled circles), with the particularity that their toxicity decreases earlier.…”

Acceleration of α‐synuclein aggregation by homologous peptides

“…The chemical shifts of the amides in fresh G68E exhibit small dispersion in the 1 H dimension (Fig. 5A), suggesting that G68E is a natively unstructured protein similar to WT a-Syn [26]. Incubation of G68E for 7 days has no significant effect on the HSQC spectrum ( Fig.…”

Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins

“…[16][17][18] It is therefore important to precisely evaluate the effect of PQQ on the cytotoxicity of amyloid proteins in developing a viable therapeutic strategy, because if the aggregates formed as a result of the prevention of fibril formation are more toxic than the fibrils formation of less than 80% and 60% of the fibrils formed in the absence of PQQ and the lag time calculated from fitting-curve was increased to 5.8 h and 7.3 h, respectively.…”