Potential Effect of Post-Transcriptional Substitutions of Tyrosine for Cysteine Residues on Transformation of Amyloidogenic Proteins.

The review considers the reasons and consequences of post-transcriptional tyrosine substitutions for cysteine residues. Main attention is paid to the Tyr/Cys substitutions that arise during gene expression in bacterial systems at the stage of protein translation as a result of misrecognition of the similar mRNA codons. Notably, translation errors generally occur relatively rarely - from 10-4 to 10-3 errors per codon for E. coli cells, but in some cases the error rate increases significantly. For example, this is typical for certain pairs of codons, when the culture conditions change or in the presence of antibiotics. Thus, with overproduction of the recombinant human alpha-synuclein in E. coli cells, the content of the mutant form with the replacement of Tyr136 (UAC codon) with a cysteine residue (UGC codon) can reach 50%. Possible reasons for the increased production of alpha-synuclein with the Tyr136Cys substitution are considered, as well as consequences of the presence of mutant forms in preparations of amyloidogenic proteins when studying their pathological transformation in vitro. A separate section is devoted to the Tyr/Cys substitutions occurring due to mRNA editing by adenosine deaminases, which is typical for eukaryotic organisms, and the possible role of this process in the amyloid transformation of proteins associated with neurodegenerative diseases.

Modification of Glyceraldehyde-3-Phosphate Dehydrogenase with Nitric Oxide: Role in Signal Transduction and Development of Apoptosis.

This review focuses on the consequences of GAPDH S-nitrosylation at the catalytic cysteine residue. The widespread hypothesis according to which S-nitrosylation causes a change in GAPDH structure and its subsequent binding to the Siah1 protein is considered in detail. It is assumed that the GAPDH complex with Siah1 is transported to the nucleus by carrier proteins, interacts with nuclear proteins, and induces apoptosis. However, there are several conflicting and unproven elements in this hypothesis. In particular, there is no direct confirmation of the interaction between the tetrameric GAPDH and Siah1 caused by S-nitrosylation of GAPDH. The question remains as to whether the translocation of GAPDH into the nucleus is caused by S-nitrosylation or by some other modification of the catalytic cysteine residue. The hypothesis of the induction of apoptosis by oxidation of GAPDH is considered. This oxidation leads to a release of the coenzyme NAD+ from the active center of GAPDH, followed by the dissociation of the tetramer into subunits, which move to the nucleus due to passive transport and induce apoptosis. In conclusion, the main tasks are summarized, the solutions to which will make it possible to more definitively establish the role of nitric oxide in the induction of apoptosis.

Differential Analysis of A-to-I mRNA Edited Sites in Parkinson's Disease.

Parkinson's disease (PD) is a widespread neuronal degenerative disorder with unexplored etiology. It is associated with various pathological events. In particular, the prefrontal cortex Brodmann area 9 (BA9) region is affected in PD. This frontal lobe brain region plays an important role in cognitive, motor, and memory-related functions. BA9 develops Lewy bodies in PD patients and shows essential changes in transcriptome and proteome, connected with mitochondria related pathways, protein folding pathways, and metallothioneins. Recently, altered adenosine to inosine mRNA editing patterns have been detected in various neurological pathologies. In this article, we present an investigation of differences in A-to-I RNA editing levels and specificity of mRNA editing sites in brain tissues of healthy and PD patients based on RNA sequencing data. Overall, decreased editing levels in the brains of PD patients were observed, potential editing sites with altered editing during PD were identified, and the role of different adenosine deaminases in this process was analyzed.