Prion Protein Prnp Research Articles

Mechanisms of Non-coenzyme Action of Thiamine: Protein Targets and Medical Significance.

Thiamine (vitamin B1) is a precursor of the well-known coenzyme of central metabolic pathways thiamine diphosphate (ThDP). Highly intense glucose oxidation in the brain requires ThDP-dependent enzymes, which determines the critical significance of thiamine for neuronal functions. However, thiamine can also act through the non-coenzyme mechanisms. The well-known facilitation of acetylcholinergic neurotransmission upon the thiamine and acetylcholine co-release into the synaptic cleft has been supported by the discovery of thiamine triphosphate (ThTP)-dependent phosphorylation of the acetylcholine receptor-associated protein rapsyn, and thiamine interaction with the TAS2R1 receptor, resulting in the activation of synaptic ion currents. The non-coenzyme regulatory binding of thiamine compounds has been demonstrated for the transcriptional regulator p53, poly(ADP-ribose) polymerase, prion protein PRNP, and a number of key metabolic enzymes that do not use ThDP as a coenzyme. The accumulated data indicate that the molecular mechanisms of the neurotropic action of thiamine are far broader than it has been originally believed, and closely linked to the metabolism of thiamine and its derivatives in animals. The significance of this topic has been illustrated by the recently established competition between thiamine and the antidiabetic drug metformin for common transporters, which can be the reason for the thiamine deficiency underlying metformin side effects. Here, we also discuss the medical implications of the research on thiamine, including the role of thiaminases in thiamine reutilization and biosynthesis of thiamine antagonists; molecular mechanisms of action of natural and synthetic thiamine antagonists, and biotransformation of pharmacological forms of thiamine. Given the wide medical application of thiamine and its synthetic forms, these aspects are of high importance for medicine and pharmacology, including the therapy of neurodegenerative diseases.

Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection.

The prion protein PRNP has been centrally implicated in the transmissible spongiform encephalopathies (TSEs), but its normal physiological role remains obscure. We highlight emerging evidence that PRNP displays antimicrobial activity, inhibiting the replication of multiple viruses, and also interacts directly with Alzheimer’s disease (AD) amyloid-β (Aβ) peptide whose own antimicrobial role is now increasingly secure. PRNP and Aβ share share membrane-penetrating, nucleic acid binding, and antiviral properties with classical antimicrobial peptides such as LL-37. We discuss findings that binding of abnormal nucleic acids to PRNP leads to oligomerization of the protein, and suggest that this may be an entrapment and sequestration process that contributes to its antimicrobial activity. Some antimicrobial peptides are known to be exploited by infectious agents, and we cover evidence that PRNP is usurped by herpes simplex virus (HSV-1) that has evolved a virus-encoded ‘anti-PRNP’.unction. These findings suggest that PRNP, like LL-37 and Aβ, is likely to be a component of the innate immune system, with implications for the pathoetiology of both AD and TSE.

Polymorphism of the prion protein gene (PRNP) in Polish Merino and Suffolk sheep flocks

The aim of the study was to investigate the distribution of prion protein PRNP alleles in flocks of Polish Merino and Suffolk sheep. The research was conducted in 2012-2017 on ewes and rams kept in the Golina Wielka sheepfold (Greater Poland Voivodeship, Poland). All animals (264 ♀ and 64 ♂ Polish Merino; 98 ♀ and 73 ♂ Suffolk) were up to one year old. PRNP gene polymorphism was identified in the sheep. The frequency of scrapie alleles and genotypes was found to be highly significantly influenced by the breed and significantly influenced by the year in the case of Polish Merino sheep. Five alleles (ALRR, ALRQ, ALHQ, AFRQ and VLRQ) were detected in Polish Merino sheep, leading to the identification of 10 PRNP genotypes. In the Suffolk breed, three alleles (ALRR, ALRQ and ALHQ) and three genotypes were identified. In the Polish Merino breed, the frequency of the ALRR/ALRQ genotype was high and was the highest among all genotypes, followed by ALRR/ALRR. The level of genotypes containing valine at codon 136 was very low. In the Suffolk breed, the frequency of the ALRR/ALRR genotype was very high, and there were no alleles with valine at codon 136. In addition, in Polish Merino sheep, phenylalanine at codon 141 was detected only in the AFRQ allele, which appeared in two genotypes (in combination with ALRR and ALRQ).