{"id":11447,"date":"2024-07-25T00:29:08","date_gmt":"2024-07-24T23:29:08","guid":{"rendered":"https:\/\/www.blopig.com\/blog\/?p=11447"},"modified":"2024-07-25T00:30:17","modified_gmt":"2024-07-24T23:30:17","slug":"deliberately-misfolding-prions-to-find-the-golden-thread","status":"publish","type":"post","link":"https:\/\/www.blopig.com\/blog\/2024\/07\/deliberately-misfolding-prions-to-find-the-golden-thread\/","title":{"rendered":"Deliberately misfolding prions to find the golden thread."},"content":{"rendered":"\n

Prion are both fascinating and terrifying. They occur naturally and have a purpose, but what that purpose is we’re still not entirely sure. Gene-knockout mice which no longer code for the prion protein do live, but they ain’t born typical.<\/p>\n\n\n\n

The endogenous form of the prion protein (PrPC<\/sup>) can, through currently unknown mechanisms, take a different conformation, the pathogenic PrPSc<\/sup>. PrPSc<\/sup> is responsible for fatal, rapidly progressing neurodegenerative disorders which in many cases can jump species.<\/p>\n\n\n\n

At OPIG, we recently discussed a remarkably rigorous series of experiments outlined in the paper “A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions<\/a>” Whilst deliberately creating new pathogenic prions may seem and odd thing to wish to achieve, the authors aimed to determine if there was a golden thread linking “infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids”.<\/p>\n\n\n\n\n\n\n\n

They collected data from GenBank, DNAZoo and even tissue samples, resulting in a dataset of 382 sequences. As you can’t simply wait around waiting for PrPC<\/sup> to spontaneously misfold, these were exposed to PMSA <\/a>(Protein Misfolding Shaking Amplification) and with multiple repeats, they measured how many cycles were required before PrPSc<\/sup> was detected, thus giving a score for each sequence and how likely it is to spontaneously misfold. The prions generated using were validated for infectivity by inoculating a highly susceptible animal model. If you’re a screaming hairy armadillo<\/a>, good news, your prions are remarkably resistant to misfolding<\/a>.<\/p>\n\n\n\n

The authors also produced the PrPdex<\/a> a database holding (at the time of writing) the PrP sequences for 725 mammal species and for each species detailing “amino acid sequences and meticulous in vitro analyses assessing their propensity for spontaneous misfolding. Additionally, the database includes ranked lists of their relative abilities to adopt a pathogenic conformation, outcomes of in vitro infectivity assays, and in silico structural predictions of their native forms, along with stability information”.<\/p>\n\n\n\n

Despite the sterling work preformed, alas there is not yet an obvious commonality. \u201c..an absence of correlation of specific taxonomic orders with misfolding propensity\u201d Their conclusion drawn from this being “..the idea that sequence similarity has a seemingly minor influence on spontaneous misfolding propensity, and points towards a major influence of specific changes rather than the mere quantity of variations.” The thermal stability of the prions were also considered, but \u201cNo correlation was observed between the predicted thermodynamic stability and the propensity to misfold\u201d.
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Prion are both fascinating and terrifying. They occur naturally and have a purpose, but what that purpose is we’re still not entirely sure. Gene-knockout mice which no longer code for the prion protein do live, but they ain’t born typical. The endogenous form of the prion protein (PrPC) can, through currently unknown mechanisms, take a […]<\/p>\n","protected":false},"author":15,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"nf_dc_page":"","wikipediapreview_detectlinks":true,"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"ngg_post_thumbnail":0,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[228,202],"tags":[13,167],"ppma_author":[507],"class_list":["post-11447","post","type-post","status-publish","format-standard","hentry","category-protein-structure","category-proteins","tag-journal-club","tag-prions"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"authors":[{"term_id":507,"user_id":15,"is_guest":0,"slug":"eoin","display_name":"Eoin Malins","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/e91a9cf8b77625a1bc34e56f5dc36439a1f61476804b087e5b47554425879210?s=96&d=mm&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/11447","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/comments?post=11447"}],"version-history":[{"count":4,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/11447\/revisions"}],"predecessor-version":[{"id":11483,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/11447\/revisions\/11483"}],"wp:attachment":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/media?parent=11447"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/categories?post=11447"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/tags?post=11447"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=11447"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}