Vitamins K interact with N-terminus α-synuclein and modulate the protein fibrillization in vitro. Exploring the interaction between quinones and α-synuclein.
In the last decades, a series of compounds, including quinones and polyphenols, has been described as having anti-fibrillogenic action on α-synuclein (α-syn) whose aggregation is associated to the pathogenesis of Parkinson's disease (PD). Most of these molecules act as promiscuous anti-amyloidogenic agents, interacting with the diverse amyloidogenic proteins (mostly unfolded) through non-specific hydrophobic interactions. Herein we investigated the effect of the vitamins K (phylloquinone, menaquinone and menadione), which are 1,4-naphthoquinone (1,4-NQ) derivatives, on α-syn aggregation, comparing them with other anti-fibrillogenic molecules such as quinones, polyphenols and lipophilic vitamins. Vitamins K delayed α-syn fibrillization in substoichiometric concentrations, leading to the formation of short, sheared fibrils and amorphous aggregates, which are less prone to produce leakage of synthetic vesicles. In seeding conditions, menadione and 1,4-NQ significantly inhibited fibrils elongation, which could be explained by their ability to destabilize preformed fibrils of α-syn. Bidimensional NMR experiments indicate that a specific site at the N-terminal α-syn (Gly31/Lys32) is involved in the interaction with vitamins K, which is corroborated by previous studies suggesting that Lys is a key residue in the interaction with quinones. Together, our data suggest that 1,4-NQ, recently showed up by our group as a potential scaffold for designing new monoamine oxidase inhibitors, is also capable to modulate α-syn fibrillization in vitro.
Department of Physical Chemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
Fernanda Luna
FL
da Silva
Eduardo
E
Coelho Cerqueira
Mônica Santos
MS
de Freitas
Daniela Leão
DL
Gonçalves
Lilian Terezinha
LT
Costa
Cristian
C
Follmer
D000933:Antifibrinolytic Agents; D002467:Cell Nucleus / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D009285:Naphthoquinones / Q000494:pharmacology; D009454:Neurofibrils / Q000187:drug effects*; D011809:Quinones / Q000494:pharmacology*; D014812:Vitamin K / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D010837:Vitamin K 1 / Q000494:pharmacology; D024482:Vitamin K 2 / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D000933:Antifibrinolytic Agents; D009285:Naphthoquinones; D011809:Quinones; D051844:alpha-Synuclein; D024482:Vitamin K 2; D014812:Vitamin K; D024483:Vitamin K 3; D010837:Vitamin K 1; C035342:1,4-naphthoquinone