Vitamins K interact with N-terminus α-synuclein and modulate the protein fibrillization in vitro. Exploring the interaction between quinones and α-synuclein

Abstract

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.

Cross Dimerization of Amyloid-β and αSynuclein Proteins in Aqueous Environment: A Molecular Dynamics Simulations Study

“…We note here that Lys specific molecular tweezers have been reported to be capable of inhibiting the aggregation of various amyloidogenic peptides [81]–[84]. 1,4-napthoquinone based inhibitors were also found to interact with Lys residues and efficiently reduced the fibrilisation propensity of αSyn [85]. Thus, our observation of the importance of the Lys repeats in the cross dimerization may be used for designing drugs targeted at inhibiting A β -αSyn co-assembly.…”

Oxidative stress and Parkinson’s disease

“…Some studies have demonstrated a regulatory role for quinone formation in DA neurons in the L-DOPA-treated PD model induced by neurotoxins and in methamphetamine neurotoxicity ( Asanuma et al, 2003 ; Miyazaki et al, 2006 ; Ares-Santos et al, 2014 ). DA quinones can modify a number of PD-related proteins, such as α-synuclein (α-syn), parkin, DJ-1, Superoxide dismutase-2 (SOD2), and UCH-L1 ( Belluzzi et al, 2012 ; Girotto et al, 2012 ; da Silva et al, 2013 ; Hauser et al, 2013 ; Toyama et al, 2014 ; Zhou et al, 2014 ) and have been shown to cause inactivation of the DA transporter (DAT) and the TH enzyme ( Kuhn et al, 1999 ; Whitehead et al, 2001 ), as well as mitochondrial dysfunction ( Lee et al, 2003 ), alterations of brain mitochondria ( Gluck and Zeevalk, 2004 ) and dysfunction in Complex I activity ( Jana et al, 2007 , 2011 ; Van Laar et al, 2009 ). Additionally, DA quinones can be oxidized to aminochrome, whose redox-cycling leads to the generation of the superoxide radical and the depletion of cellular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH), which ultimately forms the neuromelanin ( Sulzer et al, 2000 ) known to be accumulated in the SNpc of the human brain ( Ohtsuka et al, 2013 , 2014 ; Plum et al, 2013 ).…”

Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health

“…84 Vitamin K has also been shown to have a beneficial role in the modulation of α-synuclein fibrillization, associated with PD. 85 Increased dietary vitamin K intake has been associated with less severe subjective memory complaints in the elderly. 86 Vitamin B synthesis increases as the intestinal microbiota are being established 87 with deficiencies leading to serious neurological disorders including beri-beri, polyneuropathy and cerebellar ataxia.…”