Neuronal Proteins as Targets of 3-Hydroxykynurenine: Implications in Neurodegenerative Diseases

Abstract

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.

Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease

“…A clinical study of suicide attempts shows a decrease in cerebrospinal fluid and blood PIC and a simultaneous decrease in the PIC/QUIN ratio, and the SNP rs2121337 minor C allele of ACMSD, associated with an increase in cerebrospinal fluid QUIN, is more prevalent in suicide attempts [ 143 ]. Other intermediate products of KP, such as 3-HK [ 144 ], 3-HAA [ 145 ] and AA, have been found to be involved in complex pro-oxidant and antioxidant processes in the CNS [ 111 ], which may cause neuronal damage. Some byproducts of the KP such as XA and CA have been found to be neuroactive [ 146 ].…”

The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

“…Similarly, a significant microglia/macrophage activation has been described already in the first few weeks of treatment, which persists up to five weeks during the demyelination period in the CPZ animal model [ 35 , 36 ]. The dysregulation of TRP-KYN metabolism is significantly associated with neurodegenerative processes, especially via microglia activation [ 75 , 76 , 77 ]. Furthermore, the correlation between microglial activation and low 3-HK levels may be ascribed to the genetic variability of the enzymes, the locational difference in enzyme activity in the body, and the resultant difference in metabolite levels, employed in TRP-KYN metabolism [ 68 , 78 ].…”

“…In contrast, 3-HK and QUIN are considered neurotoxic metabolites at least in certain concentrations and environments, inducing cell death by various excitotoxic processes [ 75 , 96 , 97 ]. Recently, an increasing amount of evidence highlighted that 3-HK is not always toxic, because 3-HK together with 3-HANA may contribute to the regulation of the redox balance of brain tissue and prevent further damage [ 75 , 98 , 99 ]. Therefore, 3-HK is a controversial metabolite, as it can function as a scavenger but promote oxidative damage, depending on the redox environment, pH, or cell type, among others [ 99 ].…”

Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light induced damage in Drosophila

“…While conjugation of 3OH-K to proteins reduces free, toxic 3OH-K, at the same time this modification can alter the function of proteins and can convert them to harmful variants. For example, 3OH-K conjugation to Aβ peptides and peptides derived from α-synuclein was suggested to be related to neurodegeneration (Capucciati, Galliano et al, 2019). In contrast, 3OH-K conjugated to the human eye lens protein (Staniszewska & Nagaraj, 2005) and was detected in normal aged human lenses but not in damaged (cataract) lenses (Korlimbinis & Truscott, 2006).…”