Neuronal Proteins as Targets of 3-Hydroxykynurenine: Implications in Neurodegenerative Diseases.
Andrea CapucciatiMonica GallianoLuigi BubaccoLuigi ZeccaLuigi CasellaEnrico MonzaniStefania NicolisPublished in: ACS chemical neuroscience (2019)
The neurotoxic activity of the tryptophan metabolite 3-hydroxykynurenine (3OHKyn) in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, is related to oxidative stress and 3OHKyn interaction with cellular proteins. The pattern of protein modification induced by 3OHKyn involves the nucleophilic side chains of Cys, His, and Lys residues, similarly to the one promoted by dopamine and other catecholamines. In the present work, we have analyzed the reactivity of 3OHKyn toward the neuronal targets α-synuclein (and its N-terminal fragments 1-6 and 1-15) and amyloid-β peptides (1-16 and 1-28) and characterized the resulting conjugates through spectrometric (LC-MS/MS) and spectroscopic (UV-vis, fluorescence, NMR) techniques. The amino acid residues of α-synuclein and amyloid-β peptides involved in derivatizations by 3OHKyn and its autoxidation products (belonging to the xanthommatin family) are Lys and His, respectively. The pattern of protein modification is expanded in the conjugates obtained in the presence of the metal ions copper(II) or iron(III), reflecting a more oxidizing environment that in addition to adducts with protein/peptide residues also favors the fragmentation of the protein. These results open the perspective to using the 3OHKyn-protein/peptide synthetic conjugates to explore their competence to activate microglia cell cultures as well as to unravel their role in neuroinflammatory conditions.
Keyphrases
- amino acid
- oxidative stress
- magnetic resonance
- high resolution
- binding protein
- single cell
- metabolic syndrome
- ischemia reperfusion injury
- dna damage
- signaling pathway
- mass spectrometry
- mesenchymal stem cells
- small molecule
- ms ms
- blood brain barrier
- cognitive decline
- bone marrow
- heat shock protein
- molecular dynamics simulations
- tandem mass spectrometry
- gas chromatography