Amyloids or prions? That is the question

Sabaté, Raimon; Rousseau, Frédéric; Schymkowitz, Joost; Batlle, Cristina; Ventura, Salvador

doi:10.1080/19336896.2015.1053685

Cited by 35 publications

(37 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we essayed a new perspective on the effect of polymorphisms in goat prion protein stability computationally. Prion protein stability and the process of prion disease development have been linked to the structural alternation of prion protein to potentially amyloid forms 36,37 .…”

Section: Discussionmentioning

confidence: 99%

“…PHGGSRD (0.008) was predicted to have lower amyloidogenicity propensity than the wild type sequence PHGGGWG (0.096). As some proportion of amino acid sequence balance intrinsic amyloid formation and unwanted nucleation, these variants may create favourable conditions in the avoidance of non-physiologic folding 36,38 .Hotspot sequences with the H159 variant exhibited higher amyloidogenicity propensity than the wild type. The relatively higher destabilizing effect of H159 could be the potential reason why heptapeptides that included H159 had higher amyloidogenicity than other novel variants.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

View full text Add to dashboard Cite

Scrapie is a lethal neurodegenerative disease of sheep and goats caused by the misfolding of the prion protein. Variants such as M142, D145, S146, H154, Q211, and K222 were experimentally found to increase resistance or extend scrapie incubation period in goats. We aimed to identify polymorphisms in the Afar and Arsi-Bale goat breeds of Ethiopia and computationally assess the effect of variants on prion protein stability. In the present study, four non-synonymous novel polymorphisms G67S, W68R, G69D, and R159H in the first octapeptide repeat and the highly conserved C-terminus globular domain of goat PrP were detected. The resistant genotype, S146, was detected in >50% of the present population. The current study population showed a genetic diversity in Ethiopian goat breeds. In the insilico analysis, the R68 variant was predicted to increase stability while S67, D69, and H159 decrease the stability of prion protein. The new variants in the octapeptide repeat motif were predicted to decrease amyloidogenicity but H159 increased the hotspot sequence amyloidogenic propensity. These novel variants could be the source of conformational flexibility that may trigger the gain or loss of function by prion protein. Further experimental study is required to depict the actual effects of variants on prion protein stability. Prion diseases are lethal neurodegenerative disease of humans and animals caused by the misfolding of prion protein 1. Despite being rare, the diseases are lethal and have resulted in huge animal loss over a course of time in several countries 2. The oldest prion disease is scrapie that affects small ruminants 3,4. Though the exact pathomechanism is not yet known, predisposing genetic variants have been documented in different species 5. A wide range of polymorphisms have been identified in goats either as protective or susceptible alleles. A recent review reported the presence of more than 50 polymorphisms in goat prion protein-coding gene (PRNP) 6. Among the variants, G127S, M142I, H143R, N146S, R154H, Q222K, and S240P are the most common substitutions worldwide 7,8. Similarly, R139S in Algeria 9 , A116V in Tanzania 10 , G134E and Q163P in Turkey 11 and G127A and T193I in Ethiopia 12 were novel (at the time of the report) substitutions discovered in the respective area of study. Alleles such as M142, D145, S146, H154, Q211, and K222 were experimentally found to either extend scrapie incubation period or increase resistance 8,13-16. Experimental studies reported the link between sequence variation in the functional domains of prion protein and scrapie disease development 17,18. Substitutions in the palindrome and glycine-rich motifs were identified to affect amyloid fibril formation 19. Although the C terminal globular domain is often involved in the PrP c to PrP Sc conversion process, octapeptide repeat regions are also known to influence the structural dynamics of prion protein. Insertion or deletion of octapeptide repeat for example, induce disease phenotypes 20. According to the FAOSTAT 2017 report, 3...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These domains tend to have low amino acid diversity with repeating sequences that sometimes form prion‐like domains. Prions such as the N‐terminus of yeast Sup35 were first described to be enriched in glutamine and asparagine and to promote amyloid states. The development of the PrionW software (https://omictools.com/prionw-tool) allowed the discovery of many prion forming domains in human proteins, including several heterogeneous nuclear ribonucleoproteins (hnRNPs) that are dysregulated in neurodegenerative diseases, such as familial amyotrophic lateral sclerosis (fALS) .…”

Section: An Overview Of Mechanisms Driving Formation Of Membraneless mentioning

confidence: 99%

Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells

Rabouille

2019

Traffic

View full text Add to dashboard Cite

In cells at steady state, two forms of cell compartmentalization coexist: membrane‐bound organelles and phase‐separated membraneless organelles that are present in both the nucleus and the cytoplasm. Strikingly, cellular stress is a strong inducer of the reversible membraneless compartments referred to as stress assemblies. Stress assemblies play key roles in survival during cell stress and in thriving of cells upon stress relief. The two best studied stress assemblies are the RNA‐based processing‐bodies (P‐bodies) and stress granules that form in response to oxidative, endoplasmic reticulum (ER), osmotic and nutrient stress as well as many others. Interestingly, P‐bodies and stress granules are heterogeneous with respect to both the pathways that lead to their formation and their protein and RNA content. Furthermore, in yeast and Drosophila, nutrient stress also leads to the formation of many other types of prosurvival cytoplasmic stress assemblies, such as metabolic enzymes foci, proteasome storage granules, EIF2B bodies, U‐bodies and Sec bodies, some of which are not RNA‐based. Nutrient stress leads to a drop in cytoplasmic pH, which combined with posttranslational modifications of granule contents, induces phase separation.

show abstract

“…Even more important, in contrast to non-prion amyloids, this work also highlights the importance of the N-rich disordered amino acid background. On the one hand, this background ensures solubility of the prion protein to avoid oversensitive aggregation induction (Sabate et al, 2015), while on the other hand, it also drives the brittleness of prion fibrils once they form. Brittleness has been put forward as a crucial prion property (Tanaka et al, 2006), and Marchante and colleagues (Marchante et al, 2017) highlighted the importance of aggregate size and concentration in terms of prion induction in the Sup35 case.…”

Section: Discussionmentioning

confidence: 99%