Dataset Information

Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion.

ABSTRACT: Amyloid formation is associated with many incurable diseases. For some of these, sporadic cases are much more common than familial ones. Some reports point to the role of somatic cell mosaicism in these cases via origination of amyloids in a limited number of cells, which can then spread through tissues. However, specific types of sporadic mutations responsible for such effects are unknown. In order to identify mutations capable of increasing the de novo appearance of amyloids, we searched for such mutants in the yeast prionogenic protein Sup35. We introduced to yeast cells an additional copy of the SUP35 gene with mutated amyloidogenic domain and observed that some nonsense mutations increased the incidence of prions by several orders of magnitude. This effect was related to exposure at the C-terminus of an internal amyloidogenic region of Sup35. We also discovered that SUP35 mRNA could undergo splicing, although inefficiently, causing appearance of a shortened Sup35 isoform lacking its functional domain, which was also highly prionogenic. Our data suggest that truncated forms of amyloidogenic proteins, resulting from nonsense mutations or alternative splicing in rare somatic cells, might initiate spontaneous localized formation of amyloids, which can then spread, resulting in sporadic amyloid disease.

SUBMITTER: Dergalev AA

PROVIDER: S-EPMC7913716 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion.

Dergalev Alexander A AA Urakov Valery N VN Agaphonov Michael O MO Alexandrov Alexander I AI Kushnirov Vitaly V VV

International journal of molecular sciences 20210203 4

Amyloid formation is associated with many incurable diseases. For some of these, sporadic cases are much more common than familial ones. Some reports point to the role of somatic cell mosaicism in these cases via origination of amyloids in a limited number of cells, which can then spread through tissues. However, specific types of sporadic mutations responsible for such effects are unknown. In order to identify mutations capable of increasing the de novo appearance of amyloids, we searched for s ...[more]

PMID: 33546497

Similar Datasets

Project description:Nonsense Mediated Decay (NMD) degrades transcripts that contain a premature STOP codon resulting from mistranscription or missplicing. However NMD's surveillance of gene expression varies in efficiency both among and within human genes. Previous work has shown that the intron content of human genes is influenced by missplicing events invisible to NMD. Given the high rate of transcriptional errors in eukaryotes, we hypothesized that natural selection has promoted a dual strategy of "prevention and cure" to alleviate the problem of nonsense transcriptional errors. A prediction of this hypothesis is that NMD's inefficiency should leave a signature of "transcriptional robustness" in human gene sequences that reduces the frequency of nonsense transcriptional errors. For human genes we determined the usage of "fragile" codons, prone to mistranscription into STOP codons, relative to the usage of "robust" codons that do not generate nonsense errors. We observe that single-exon genes have evolved to become robust to mistranscription, because they show a significant tendency to avoid fragile codons relative to robust codons when compared to multi-exon genes. A similar depletion is evident in last exons of multi-exon genes. Histone genes are particularly depleted of fragile codons and thus highly robust to transcriptional errors. Finally, the protein products of single-exon genes show a strong tendency to avoid those amino acids that can only be encoded using fragile codons. Each of these observations can be attributed to NMD deficiency. Thus, in the human genome, wherever the "cure" for nonsense (i.e. NMD) is inefficient, there is increased reliance on the strategy of nonsense "prevention" (i.e. transcriptional robustness). This study shows that human genes are exposed to the deleterious influence of transcriptional errors. Moreover, it suggests that gene expression errors are an underestimated phenomenon, in molecular evolution in general and in selection for genomic robustness in particular.

Project description:Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

Dataset Information

Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion.

Publications

Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets