Characterization of mutations in <em>PRNP</em> (prion) gene and their possible roles in neurodegenerative diseases

Abstract

Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis.

Clinical features and genetic characteristics of two Chinese pedigrees with fatal family insomnia

“…Their clinical phenotype depends on the presence of Met or valine (Val) at codon 129. FFI is correlated to the Met allele [13]. FFI patients with heterozygous (Met-Val) mutation have a longer mean survival time than those with homozygous (Met-Met) [3].…”

A case report of genetic prion disease with two different PRNP variants

“…Missense variants in PRNP have been reported in patients with genetic prion disease. The c.628G>A (p.V210I) variant has been reported in many patients with prion disease (Bagyinszky, Giau, Youn, An, & Kim, 2018;Biljan et al.,…”

A New Take on Prion Protein Dynamics in Cellular Trafficking

“…However, the blockage of both canonical endocytic pathways, clathrin- and caveolin-mediated, presented discrepant outcomes according to early or late stages of infection and different PrP Sc variant strains [ 117 ], denoting that there are plenty of unknown mechanisms through which PrP Sc may act. As the PRNP gene is known to show several distinct mutations [ 118 ], it would be relevant to ascertain whether these differences in endocytosis might occur due to these various types of genomic alterations. Interestingly, PrP C mutants at the N-terminal site present a lack of copper-mediated endocytosis, which could lead to neuronal apoptosis and symptoms of prion diseases as if they were infected with PrP Sc , supporting the importance of the endocytic pathway for PrP Sc cell–cell transmission [ 31 ].…”