Protein Misfolding and Cardiac Disease
(2008)
Hat tip to Dr. Jonathan J Couey, C/O Gigaohm Biological.
https://m.twitch.tv/videos/1274929645
Any extracts used in the following article are for non commercial research and educational purposes only and may be subject to copyright from their respective owners.
Background
Mistranslation of modified spike protein expressing mRNA could theoretically lead to protein misfolding, leading to pathophysiological sequalae.
NB this doesn't remove other possible causes of Vaccine-induced Inflammatory Heart Disease or failure as discussed previously.
Pseudouridinylation of mRNA coding sequences alters translation (2019)
Abstract
Chemical modifications of RNAs have long been established as key modulators of nonprotein-coding RNA structure and function in cells. There is a growing appreciation that messenger RNA (mRNA) sequences responsible for directing protein synthesis can also be posttranscriptionally modified. The enzymatic incorporation of mRNA modifications has many potential outcomes, including changing mRNA stability, protein recruitment, and translation. We tested how one of the most common modifications present in mRNA coding regions, pseudouridine (Ψ), impacts protein synthesis using a fully reconstituted bacterial translation system and human cells. Our work reveals that replacing a single uridine nucleotide with Ψ in an mRNA codon impedes amino acid addition and EF-Tu GTPase activation. A crystal structure of the Thermus thermophilus 70S ribosome with a tRNAPhe bound to a ΨUU codon in the A site supports these findings. We also find that the presence of Ψ can promote the low-level synthesis of multiple peptide products from a single mRNA sequence in the reconstituted translation system as well as human cells, and increases the rate of near-cognate Val-tRNAVal reacting on a ΨUU codon. The vast majority of Ψ moieties in mRNAs are found in coding regions, and our study suggests that one consequence of the ribosome encountering Ψ can be to modestly alter both translation speed and mRNA decoding.
translation pseudouridine mRNA modification ribosome
https://www.pnas.org/content/116/46/23068
Protein Misfolding and Cardiac Disease
Abstract
Numerous neurodegenerative diseases are characterized by the accumulation of misfolded amyloidogenic proteins. Recent data indicate that a soluble pre-amyloid oligomer (PAO) may be the toxic entity in these diseases and the visible amyloid plaques, rather than causing the disease, may simply mark the terminal pathology. In prior studies, we observed PAO in the cardiomyocytes of many human heart failure samples. To test the hypothesis that cardiomyocyte-restricted expression of a known PAO is sufficient to cause heart failure, transgenic mice were created expressing polyglutamine repeats of 83 (PQ83) or 19 (PQ19).Long PQ repeats (>50) form PAOs and result in neurotoxicity in Huntingtonâs disease, whereas shorter PQ repeats are benign. PQ83 expression caused the intracellular accumulation of PAOs and aggregates leading to cardiomyocyte death and heart failure. Evidence of increased autophagy and necrosis accompanied the PQ83 cardiomyocyte pathology. The data confirm that protein misfolding resulting in intracellular PAO accumulation is sufficient to cause cardiomyocyte death and heart failure.
Keywords: Protein misfolding, amyloid oligomer, heart disease, autophagy, heart, polyglutamine