Biosemiotics comprehension of PrP code and prion disease

BioSys ems 210 (2021) 104542 A ailable online 10 Sep embe 2021 0303-2647/© 2021 The Au ho s. Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Biosemio ics comp ehension o P P code and p ion disease Juan R. Coca a , * , Hasie E a˜ na b , c , Joaquín Cas illa b , d a Social Resea ch Uni in Heal h and Ra e Diseases, Uni e si y o Valladolid, Spain b Cen e o Coope a i e Resea ch in Biosciences (CIC BioGUNE), Basque Resea ch and Technology Alliance (BRTA), De io, Spain c A las Molecula Pha ma S. L., De io, Spain d IKERBASQUE, Basque Founda ion o Science, Bilbao, Spain ARTICLE INFO Keywo ds: P o ein mis olding Neu odegene a i e diseases P ion biosemio ics Biosocial ABSTRACT P ions o P P Sc (p ion p o ein, Sc apie iso o m) a e p o eins wi h an abe an h ee-dimensional con o ma ion ha p esen he abili y o al e he h ee-dimensional s uc u e o na i ely olded P P C (p ion p o ein, cellula iso o m) inducing i s abno mal olding, gi ing aise o neu ological diseases known as T ansmissible spongi o ms encephalopa hies (TSEs) o p ion diseases. In his wo k, h ough a biosemio ic s udy, we will analyze he mo- lecula code o meanings ha a e known in he molecula pa hway o P P C and how i is al e ed in p ion diseases. This biosemio ic code p esen s a socio-semio ic co ela e in o ganisms ha could be un a eled wi h he ul ima e goal o unde s anding he code o signs ha media es he p ocess. Finally, we will s udy ecen wo ks ha indica e possible ela ionships in he code be ween p ion p o eins and o he p o eins such as he au p o ein and alpha-synuclein o e alua e i i is possible ha he e is a semio ic expansion o he P P code and p ion diseases in he meaning ecen ly expounded by P usine , winne o he Nobel P ize o desc ibing hese unusual pa hological p ocesses. 1. In oduc ion In 1982, S anley P usine de ined p ions as p o einaceous in ec ious pa icles and as he only esponsible o T ansmissible Spongi o m En- cephalopa hies (TSE). Since his con o e sial heo y was pos ula ed, he knowledge abou hese pa icles has inc eased no ably and nowa- days he e a e many neu odegene a i e diseases, such as synucleino- pa hies and auopa hies, cha ac e ized by he p esence o endogenous mis olded p o ein agg ega es ha could sha e impo an ea u es wi h TSE causing p ions. Apa om disease-causing p o eins p one o mis- old in o sel - eplica ing amyloids, o he p o eins ha e been desc ibed able o acqui e an amyloidogenic s uc u e, which a e no ela ed o disease. These p o eins ha u ilize mis olding as a mean o egula e hei unc ion o ac i i y, a e known as unc ional amyloids and ha e been ound in e olu iona ily dis an species such as bac e ia (Gi aldo e al., 2016), ungi (Wickne e al., 2015), gas opods (Hein ich and Lindquis , 2011) and mammals (Hou e al., 2011). As he molecula mechanisms unde lying mis olding and accumula ion o such amyloidogenic p o eins a e disco e ed, he line sepa a ing in ec ious o disease-causing p ions om non-in ec ious o unc ional amyloids is ge ing blu ed (E a˜ na, 2018). The e o e, i may be possible ha all o hem sha e a gene al common biological code. The i s e idence o he exis ence o unc- ional amyloids wi h commonali ies wi h p ions a ises in 1994 om he disco e y o he so-called yeas p ions (Wickne , 1994). These p o eins showed he capaci y o be ansmi ed cell- o-cell and induce hei con o ma ion o na i ely olded coun e pa s, wha led he esea che s o include hem unde he same ca ego y as TSE-causing p ions due o hei simila au oca aly ic eplica ion mechanism. P ion diseases a e a se o ansmissible neu odegene a i e pa hol- ogies, ha can occu spo adically, be inhe i ed o acqui ed h ough di- e a y o ia ogenic exposu e o p ions. Human cellula p ion p o ein (P P C ) is a glycop o ein o 253 amino acids wi h an 85–90% homology wi h o he mammalian P P, p esen s a GPI ancho , and wo N-glyco- syla ion si es (Pa chi e al., 2011; Ba al e al., 2019). Upon mis olding h ough poo ly cha ac e ized mechanisms, he cellula p ion p o ein acqui es an abe an h ee-dimensional s uc u e called p ion o P P Sc ( om sc apie, he disease in sheep), becoming agg ega ion p one, gaining he abili y o induce his con o ma ion o he na i e p o ein, and becoming neu o oxic, which in u n leads o he de elopmen o TSE. Among hese illnesses, C eu z eld -Jakob diseases (CJD) is he mos common ype o p ionopa hy in humans. In ac , CJD can be u he classi ied in o spo adic CJD (sCJD), amilial o gene ically de e mined * Co esponding au ho . E-mail add ess: [email p o ec ed] (J.R. Coca). Con en s lis s a ailable a ScienceDi ec BioSys ems jou nal homepage: www.else ie .com/loca e/biosys ems h ps://doi.o g/10.1016/j.biosys ems.2021.104542 Recei ed 22 Janua y 2021; Recei ed in e ised o m 1 Sep embe 2021; Accep ed 7 Sep embe 2021 BioSys ems 210 (2021) 104542 2 CJD, ia ogenic CJD (iCJD) which a ise om in ec ions due o medical p ocedu es, and he a ian CJD ( CJD) which di e s om he o he s in i s zoono ic na u e and is acqui ed h ough inges ion o p ion-in ec ed ca le mea . The i s one accoun s o he 85–90% o all human CJD cases, and he second a ound 10% o he o al, while iCJD and CJD a e almos e adica ed nowadays (Pascuzzo e al., 2021; Ya us, 2011). Gene ic CJD a ise due o mu a ions in he P P C encoding gene (PRNP). This gene is loca ed on he sho a m o ch omosome 20 in humans and en ails wo exons and one in on o 13 kbp. Cu en ly, a ound 70 a ian s o his gene ha e been desc ibed (Jones and Mead, 2020). Howe e , mos o gCJD cases a e due o mu a ions E200K, V210I and V180I (Takada e al., 2017). Impo an ly, apa om disease-associa ed mu a ions, ano he polymo phism in PRNP, he p esence o aline o me hionine a codon 129, has been epo ed o exe a g ea in luence on he pa hological p ocess. In ac , hese a ian s de e mine he age o clinical onse and clinical du a ion in a subse o inhe i ed p ion diso de s (IPDs) and al e s he isk and clinical du a ion o sCJD and ia ogenic CJD (Jones and Mead, 2020). Howe e , apa om he in luence o he P P C amino acid om he hos , he mos impo an de e minan o he disease geno ype in TSE is he h ee-dimensional s uc u e o he P P Sc . The ac ha p ions can show dis inc biochemical and biological p ope ies due o di e ences in hei con o ma ions is known as he s ain phenomenon, in eminiscence o he i al s ains, and is one o he mos in iguing p ope ies o p ions. These s uc u al di e ences enable hem o p esen di e en ea u es such as a de e mina e hos ange o opism o speci ic b ain a eas (S ein and T ue, 2014). This in u n, demons a es ha he s uc u e o a p o ein encodes biological in o ma ion in absence o gene ic a ia ion, since p ions wi h iden ical amino acid sequences can show s ikingly di e en p ope ies. We ha e he e o e conside ed i impo an o analyze he biology o he p ion code and o s udy how his code helps o unde s and biological phenomena ela ed o he ac i i y o hese mis- olded p o eins and hei e ec s on social beha iou in humans. The key ole o P P C in TSE was undoub edly demons a ed h ough dele ion o PRNP in mice, which esul ed in comple e esis ance o p ion in ec ion, while es o a ion o PRNP gene also es o ed he suscep ibili y o p ion in ec ion (P iola, 2018). Howe e , al hough exp ession o hos P P C is an u e equi emen o he in ec ion, i is no su icien de e - minan o a cell o be suscep ible o p ion in ec ion, as demons a ed by cell lines which exp ess P P C bu can emain e ac o y o in ec ion (Oelschlegel e al., 2015; P iola, 2018). CJD esul s in a apidly e ol ing neu odegene a i e disease cha - ac e ized by neu onal loss, spongi o m degene a ion and as ogliosis. Likewise, deposi s o he mis olded o m o he P P a e obse ed in he b ain o hese pa ien s, wha led o he inding ha amyloidogenic p o eins could be esponsible o hese diso de s and ul ima ely o he de ini ion o p o einaceous in ec ious pa icles by P usine . Howe e , despi e he knowledge ga he ed abou p ions and he disease hey cause du ing he las decades, he molecula mechanisms leading o he mis- olding o P P C in o P P Sc emain unsol ed, impeding u he unde - s anding o he causes o non-inhe i ed and acqui ed p ion diseases. As a esul , exis ing knowledge is somewha agmen a y and limi s he possibili ies o a comple e biosemio ics analysis. Howe e , in human p ion diseases, he ela ionship be ween he biological code and i s so- cial co ela e a e clea e and could be analysed om he pe spec i e o biosemio ics. Howe e , TSE-causing p ions a e no he only p o eins ha p esen he abili y o mis old and encode in o ma ion h ough hei 3D s uc- u e. As men ioned be o e one o he mos no able examples a e yeas p ions, which a e no pa hogenic and do no comple ely i unde he de ini ion o p ions unde s ood as p o einaceous pa hogens. Ei he way, yeas p ions a e a majo line o esea ch o comp ehend he biological code o in o ma ion ansmission h ough p o ein mis olding. In his pape we pe o m a heo e ical in es iga ion o unde s and he basic elemen s o he biological code (acco ding o code biology heo y) ha could ope a e a ound hese p o einaceous pa icles which in ec ious o no , seem o be able o encode and ansmi biological in o ma ion in hei h ee-dimensional con o ma ion. 2. Code biology Be o e going in o u he de ails, i is con enien o indica e ha he code biology p oposal is based on he idea ha in li ing o ganisms we can ind a mul i ude o biological codes. They con ain meanings o g ea impo ance and will allow (in one way o ano he ) he codi ica ion o di e en s uc u es ha will esul in dis inc e ec s. In ou case, we will ocus on analysing he biology o p ions om he pe spec i e o code biology. Acco ding o his iewpoin , i can be a i med ha li ing sys- ems (also he molecula sys ems) a e semio ic en i ies in he sense ha hey ope a e unde he iadic s uc u e o sign, code, and meaning (Ba bie i, 2003; Fa ia, 2008). Fu he mo e, Ba bie i (2008a) explained ha all semio ic sys em is con igu a ed by a e alogy: signs, meaning, code, and codemake . Acco ding o his, a semio ic sys em is always made o wo wo lds. On one hand is he wo ld o objec s named signs and on he o he , he wo ld o objec s ha ep esen meanings (Ba bie i, 2008a). These wo wo lds a e ela ed h ough codes, also named con en ions. The e o e, codes will be o majo ele ance in semio ic sys ems. In ac , he code has been de ined as a mapping be ween objec s o wo wo lds ha is execu ed by objec s o a hi d wo ld: he adap o s. In ac , adap o s p o ide some meanings o molecula s uc u es because hey can cause modi ica ions in p e-exis ing molecules. Howe e , we a e no pa icu- la ly in e es ed on adap o s in his wo k because, al hough hey can help in he p ocess o media ion be ween di e en biological wo lds, hey a e no o majo impo ance in e ms o p ion biosemiosis. To comp ehend he code o p ions and i s biosemiosis, is necessa y o in oduce a ou h elemen in his s uc u e: he codemake s (Ba bie i, 2008c). Ba bie i (2008a) clea ly explains ha he codemake s a e he agen s o semiosis ( o his eason we ocus ou in e es in hese molecules), while signs and meanings a e i s ins umen s. In biological sys ems, signs and meanings exis s a he molecula and biochemical le el, in u n he signs and meanings o ou cul u al wo ld anscend he molecula eali y (Ba bie i, 2008b). In o he wo ds, bio- logical sys ems con ain and gene a e signs and meanings ha can be de ec ed and ha shape li e i sel (biological and biosocial). Howe e , he cul u al wo ld is made up o sha ed signs and meanings ha ope a e in a di e en way, since i is no usually a ec ed, in a di ec way, by biological sys ems. I we exempli y his in p ions, we can indica e ha hese biological s uc u es ha e clea biosocial e ec s (neu o- degene a ions). Howe e , whe he his biosocial e ec de i es in cul- u al e ec s and, he e o e, whe he hey ha e implica ions in he collec i e way o unde s anding he wo ld is no wi hin he scope o his manusc ip , as i would be equi e a ho ough social analysis on he cul u al impac o hese diseases. Thus, we will ocus on one o he majo p oblems on code biology, ha is o de e mine i he e a e codemake -dependen en i ies, aking in o accoun ha men al signs and men al meanings do no exis s wi hou hese codemake s and include ou side a codemaking phenome- non (Ba bie i, 2008a, 2008b). As we will see below, he e is a ce ain e olu iona y co ela e in p ions. The e o e, by un a eling pa o his e olu iona y phenomenon and explo ing i s linkage wi h p ions, we will be able o app oach he de e mina ion o he elemen s (codemake s) ha gene a e he p ion code and p opose ha i could ha e o igina ed a he dawn o li e on Ea h. The biological code ope a es as a s uc u e made o genes, p o eins and ibosoids, acco ding o h ee majo elemen s o he biochemical cell ypology: geno ype, pheno ype and ibo ype (Ba bie i, 1985). This ime we a e pa icula ly in e es ed on he ibo ype. This cellula subsys em e e s o he se o ibosoids (p o eins, enzymes, and RNAs ha ac as a molecula machine y implica ed in gene and p o ein syn hesis), and hus, his hypo hesis could be closely ela ed wi h he RNA Wo ld hy- po hesis. The RNA Wo ld heo y pos ula es he exis ence o an RNA-based ecosys em as he o igin o li e, gi en ha RNA could be able J.R. Coca e al. BioSys ems 210 (2021) 104542 3 o make copies o i sel as well as showing enzyma ic ac i i y ( ibo- zymes), which would on ime e ol e o a DNA, RNA and p o ein-based eplica ion machine y. In ac , s udies on he o igin o he p imi i e biological sys ems, conside he de elopmen o ans e ence RNA which would be he necessa y adap o s o link he DNA and p o ein wo lds, as he c i ical e en in he ansi ion om an RNA wo ld o a ibonucleop o ein wo ld (Fa ias and Jos´ e, 2020). In u n, he au oca a- ly ic anabolis heo y conside s ha nucleic acids and eplica ion a e pa o he e olu ion, so he e mus ha e been a p imo dial mechanism o e olu ion independen o nucleic acids based on he au oca aly ic me abolic ep oduc ion (W¨ ach e sh¨ ause , 2006). In his p imi i e wo ld, he molecules named by Ba bie i as ibo- soids, would no need ca aly ic p ocessing o an accompanying nucleic acid. Then, hese molecules could spon aneously copy hemsel es and gene a e a new code (codemake s). Fo ha , Ba bie i seems o suppo he second hypo hesis men ioned: he anabolis heo y. Howe e , we do no in end o discuss hese hypo heses and which o hem is he closes o eali y, bu only o es ablish a amewo k o ou semio ic analysis ega ding amyloidogenic p o eins like p ions. In any case, he idea o ibosoids e e s o he p esence o molecules wi h p imi i e cha ac e - is ics in e ms o in o ma ion coding ha could be linked o he capaci y o ansmission and au oca alysis. As we shall see la e , p ions may ha e ce ain cha ac e is ics ha a e close o hose o ances al ibosoids, heo e ically p oposed by he ibo ype heo y. I is no in ended o claim ha p ions a e ibosoids. Wha we wan o show is ha p ions p esen some cha ac e is ics ha would also be p esen in hose molecules o which Ba bie i spoke: he ibosoids. Also, Ba bie i (2008b) a i ms ha i geno ype is he pilla o he- edi y, and he pheno ype is he suppo o me abolism, hen ibo ype is he codemake pilla o he cell. The biological and in o ma ional cha ac e is ics o codemake s can be acked o assess i he e could exis molecules wi h simila beha iou s inside cells. In his sense, and due o he p imi i e na u e o codemake s, i would be possible o a i m ha hose molecules wi h he capaci y o al e he code o a p e ious mole- cule a e codemake s. Ba bie i (2012, 2015) alked abou copymake s and codemake s inside i s ibo ype heo y. Copymake s a e molecules wi h he abili y o copy hemsel es and, because o ha , a e able o ansmi in o ma ion. Codemake s, in u n, a e e y ele an in he biological e olu ion because hese molecules gene a e meanings om copymake molecules. This ypology helps o elucida e he biological codes in ol ed in p ion-media ed phenomena. In ac , as we will show below, p ions use bo h codes o ansmi hemsel es and o al e ne e cell p ocesses. Hence, in he p esen case, i is no easy o delimi whe he p ions a e copymake s o codemake s. This is because hese mis olded p o eins copy hei own in o ma ion and al e p e-exis ing in o ma ion in he cell. Once in oduced he biochemical basis o p ion eplica ion o p op- aga ion and he main concep s o he semio ic sys ems, we can now an icipa e ha p ions may ope a e as copymake s by gene a ing copies o hemsel es, and as codemake s by gene a ing new biological codes o al e a ions o p e ious ones. In addi ion, we hypo hesised ha p ions also ha e e ec s by gene a ing neu onal code-b eaking mechanisms. In his sense, al e a ions in hese p o eins lead o neu odegene a ion and ha e a s ong impac on he a ec ed indi iduals and hei amilies. 3. The p ionic eplica o code Once he gene al cha ac e is ics o he code biology a e unde s ood, we will now del e, mo e speci ically, in o he heo e ical basis o he p ion code. To do so, we will s udy molecules ha could po en ially unc ion as codemake s, which a e he undamen al basis o he p ion code. In his sense, we will ocus on showing he undamen al heo e ical elemen s ha allow us o iden i y he p ion code as a eplica i e code. Weiss e al. (2016) conside ha he las uni e sal common ances o (named LUCA, o p ogeno e) is a main model o s udy ea ly e olu ion and li e’s o igin. This p ogeno e possessed a memb ane, DNA, he basic molecula machines o copying nucleic acid, and a unc ional ibosome, among o he elemen s. Ya us (2011) pos ula ed ha LUCA would need molecula sel - eplica o s and he i s one was named as he Ini ial Da winian Ances o (IDA). In o he wo ds, he sel - eplica ion mecha- nism is a p imo dial elemen in he i s s eps o li e on Ea h. We ha e seen ha he e a e heo ies ha indica e ha nucleic acids we e essen ial in he o igin o li e. O he heo ies speak ha i is eally ca abolism. Wha seems e iden is ha a he dawn o li e on Ea h he e we e molecules wi h he capaci y o sel - eplica ion. In his sense, i is easible o conside ha molecules ha ha e he capaci y o bind o o he molecules and induce hei con e sion in o s uc u al eplica es o hemsel es could ha e been o g ea e olu iona y impo ance. Di e en molecules ha e been p oposed o ope a e as he i s eplica o such as p o ein o pep ides alone (i. e. hiol- ich pep ides o amyloids, inspi ed in he unde s anding o p ions), nucleic acid alone (wha is mainly ep esen ed by he RNA Wo ld heo y) and a combina ion o bo h o nucleopep ide eplica o s (Pie e and Heddle, 2020). This idea allows us o concep ually ela e he p ion ac i i y as eplica o wi h ano he ep- lica o p oposed by Dawkins in di e en wo ks and allows us o hy- po hesize ha he mis olded p ion p o ein could be unc ionally close o he wo ld o he ibosoids men ioned abo e. Ob iously, we a e no claiming ha P P is a ibosoid, bu we in end o p opose ha p ions could be loca ed, biosemio ically, wi hin ha biological code. In his ega d, i is also in e es ing o conside he heo y p oposing ha amy- loid olding lies wi hin he o igin o p o ein olding (G eenwald and Riek 2012). This could indica e he exis ence o ano he code in which am- yloids would ha e been pi o al, no o hei sel -p opaga ing abili y bu because hey could help shed ligh on a common code o p o ein olding. Wills (2001) indica e ha he mos elemen a y o m o chemical au oca alysis is ep esen ed by equa ion A+B→2A. This equa ion also desc ibes he p ion eplica ion mechanism in mammals, in yeas and ungi. Now, acco ding o Wills, we could say ha p ions a e pa o an elemen a y mechanism o ca alysis, so i seems plausible o say ha hey a e molecules wi h ances al eminiscences and he e o e, i could be possible o conside p ions as p imi i e eplica o s. Acco ding o Richa d Dawkins he e a e molecules ha can be classi ied as eplica o s and ehicles (1976, 1982a). La e , Dawkins (1982b) explained ha eplica o s a e molecules wi h he capaci y o make copies o hemsel es (i.e., genes). Hull e al. (2001) a i med ha eplica o s con ain i e a ion possibili ies and in o ma ion. This is o say ha he own s uc u e o hese eplica o s con ains in o ma ion and hus, his s uc u e can be a code o he in o ma ion. Dawkins (1976, 1982a) also de ined ehicles, en i ies ha a e gene a ed by codi ica ion o ep- lica o s, while he eplica o s can also modi y ehicles. Fu he mo e, hese en i ies in e ac wi h he en i onmen . The concep ual de e mi- na ion made by Dawkins aises ce ain di icul ies in de e mining wha a p ion is. In his sense, p ions could be indi e en ly eplica o s and e- hicles (especially in ela ion o hose ha a e inges ed). Fo his eason, we belie e ha he concep s p oposed by Ba bie i a e mo e heu is ic, which, as we ha e said, a e hose o copymake s and codemake s. In his sense Sza hm´ a y (2000) conside p ions as molecula pheno ypic eplica o s. Now, P P Sc could be unde s ood as a codemake because i shows he capaci y o mis old P P C and con e his non-in ec i e p o ein in o an in ec i e, sel - eplica ing en i y. Bea ing his in mind, P P C could be concep ually exp essed as a ehicle o code inse in his p o ein h ough making copies o i sel (copymake ). Also, in he las decade di e en pape s ha e p o ided con incing e idence ha cellula molecules o non-p o ein na u e including RNAs and lipids could assis p ion eplica ion (Ka o cha e al., 2018). P ion p o eins he e o e, seem o show a biological code eminiscen o ances al p o eins wi h analogies o some o he p o eins ound in ungi and bac e ia. This could imply he exis ence o an e olu iona y con inuum be ween di e en o ganisms. This possible con inuum is e- lec ed in he common molecula mechanisms sha ed by a se ies o p o eins ha ha e been o en e med p ion-like p o eins. In all cases, J.R. Coca e al. BioSys ems 210 (2021) 104542 4 om bac e ia o mammalian cells, p o eins able o adop an al e na i e, no mally β-shee en iched h ee-dimensional s uc u e ha e been desc ibed, able o sel - eplica e h ough he induc ion o such s uc u e in na i e coun e pa s and o cell- o-cell mig a ion. These al e ed p o- eins acqui e no el unc ions wi h espec o hei na i ely olded coun e pa s. Fu he mo e, di e ences in such newly acqui ed p ope - ies ha e been obse ed, based on sligh ly di e en s uc u al a ange- men s, showing ha di e en in o ma ion can be encoded and ansmi ed h ough dis inc a angemen s o p o ein s uc u e. The ac ha hese closely ela ed molecula mechanisms ha e been obse ed in s ikingly e olu iona ily dis an o ganisms, as well as his phenomenon no being ela ed jus o disease, bu also o speci ic cellula unc ions, a gues in a o o a possible common o igin o he exis ence o a p imi i e biological code based on s uc u al ea angemen o epli- ca ion and ansmission o in o ma ion (E a˜ na, 2018). We know ha he pu pose o he ances al biological sys ems was no he syn hesis o speci ic p o eins because hey could no e alua e he u u e bene i s o such p o eins. Wha hey could e alua e, howe e , we e he immedia e bene i s o ibosomal machines ha we e inc eas- ingly e icien in p oducing hei s a is ical p o eins and i was o his eason ha e olu ion sys ema ically dec eased he ambigui y o he ances al gene ic code (Ba bie i, 2019). Acco ding o his sen ence, i could be possible o conside he p ionic code as a eminiscen o ha ances al biological sys em in which he ambigui y had no been ye dec eased. Replica o ’s cha ac e is ics o P P Sc and o he amyloidogenic p o- eins conduc ed Mau y (2009) o p opose he exis ence o an ‘amyloid wo ld’. In his p ebio ic model o he wo ld di e en p ebio ic in o - ma ional en i ies could ha e eme ged and hus, Mau y’s model is in line wi h he biological code p oposal o Ma cello Ba bie i. The model o Mau y has been suppo ed by Li e al. (2010) who showed ha p ions could also be subjec ed o Da winian e olu ion. Acco ding o hei esea ch, p ions a e subjec o mu a ion (e idenced by he i able changes o hei pheno ypic p ope ies) and o selec i e ampli ica ion (docu- men ed by he ise o dis inc popula ions o p ions in di e en en i- onmen s). Mau y (2018) has ecen ly explained ha a dis inc i e ea u e o amyloid o ma ion is ha he same pep ide monome can gene a e unc ionally and s uc u ally di e en amyloid con o me s. These con o me s could p opaga e and make new copies o hemsel es. Hence, he p oposed eplica ion sys em could adap o e en small changes in he ex e nal en i onmen , being consis en wi h he e olu- iona y p ocess. Mau y’s hypo hesis is ela ed o Ba bie i’s wo k and sugges s ha he exis ence o p o eins wi h p ion-like beha iou could be ela ed o hese copymake s and codemake s p esen in his ances al wo ld. I should be ecalled ha hese codemake s we e undamen al o a i m he exis ence o a possible biological code. Fu he mo e, Wickne (2016) p oposed ha al hough p ion a ian s a e p opaga ed wi h ce ain cons ancy o hei s uc u e, changes in i , and in u n in hei p ope ies, could also occu unde selec ion p essu e in mammals and yeas . Some o hese selec ion mechanisms could be c ossing a species ba ie , in which p ions a e exposed o P P C wi h di e en amino acid sequence and likely dis inc compa ibili y wi h he pa hogen, o adminis a ion o a d ug ha can block he p opaga ion o speci ic s uc u al a angemen s (Li e al., 2010; Wickne , 2016). Howe e , a ian p ope ies can change, and a mix u e o a ian s can be seg ega ed du ing p opaga ion, e en unde nonselec i e condi ions. In ag eemen wi h his, Wickne (2016) and o he s such as Collinge and Cla ke (2007), who o iginally p oposed his idea, de end he exis ence o p ions as a “p ion cloud” composed o sligh ly di e en con o me s which would be esponsible o he inal pheno ype as a whole. This model is in ended o show ha p ions (a leas yeas p ions, al hough i seems ha his model can be ex ended o TSE-causing p ions) a e no a uni o m s uc u e, bu hey ha e an a ay o ela ed sel -p opaga ing amyloid s uc u es (Ba eman and Wickne , 2013). The e o e, and ac- co ding o he “p ion cloud” model, he e is a basic p ima y code ( he one ela ed o he amyloid s uc u e) ha seems o be main ained h oughou he e olu iona y p ocess. This, as we ha e al eady said, also bea s some ela ion o an ances al p o ein beha iou , eminiscen o ha iden i ied in he ibosoid code bu no he same. The di e en heo e ical app oaches shown, allow us o a i m ha i is plausible o conside he exis ence o a p ion biological code o e en, an amyloid biological code. The undamen al cha ac e is ics o his code, as we shall see in he ollowing sec ion, a e ound in di e en o ganisms, po en ially expanding he amyloid code unde analysis o o he p o eins han TSE-causing p ions. 4. P ions in non-human o ganisms P o eins able o o m amyloids can be ound in many o ganisms such as bac e ia, ungi, yeas s and, o cou se, highe e eb a es. Amyloids a e insoluble agg ega es o p o eins, cha ac e ized by a c oss-β shee qua e na y s uc u e in which molecules in a β-s and con o ma ion a e s acked along a ilamen axis. These p ope ies a e sha ed by a a ie y o amyloid p o eins ha can agg ega e in di e en ways, depending on he speci ic p o ein and he o ganism in which i is exp essed. And while some o hem a e associa ed o pa hologies, unc ional amyloids a e also p esen in a wide a ie y o o ganisms and ul il se e al ele an cellula unc ions (He ´ as e al., 2021). Among o he s, hese unc ional amyloids can o m bio ilms in bac e ia o assis monolaye o ma ion a a su ace. In yeas , he HET-s p ion om Podospo a anse ina pa icipa es in he he e oka yon compa ibili y o neighbou ing colonies and in o he cases, he agg ega ion is also used as a mechanism o “supp ess” he unc ion o he soluble o na i ely olded iso o m o he p o ein (e.g., Cdc19), occu ing o ins ance when he yeas s a e in s ess and gene a e se e al g anules o inc ease hei su i al oppo uni ies (O zen and Riek, 2019). Mo eo e , he molecula mechanisms ha lead o he biological unc ion o HET-s p ion ha e been s udied in de ail, e ealing ha he p ion olding domain o p ion mo i o his p o ein pa icipa es in a signal ansduc ion p ocess h ough c oss alk wi h o he homologous domains om o he p o eins. This indica es ha such con o ma ional c oss alk be ween p o eins wi h amyloid o ming domains could be a common molecula mechanism sp ead h oughou se e al o ganisms, se ing p o eins wi h amyloidogenic domains in a con ex o wide biological signi icance ha goes om unc ional amyloids o disease-causing am- yloids (Riek and Saupe, 2016; Chi i and Dobson, 2017). The cy oplasmic polyadenyla ion elemen -binding (CPEB) is ano he in e es ing example o a unc ional amyloid. The amyloid-like p ope ies o his p o ein desc ibed in Aplysia, and hus named ApCPEB, has a p ion-like domain (PLD) and p esen s a simila p ocess o agg ega ion o ha o TSE-causing p ions and yeas p ions, which has led a p oposal ha his molecule associa ed wi h o ma ion o memo y is a p ion (Si e al., 2010; Glanzman, 2013). CPEB agg ega ion is due o he p ion-like domain o he p o ein, which sha es physicochemical p ope ies wi h domains de ec ed in well cha ac e ized amyloidogenic p o eins. How- e e , his domain a ies in i s sequences ac oss species and in ac , he e a e simili udes be ween Aplysia CPEB (ApCPEB) PLD and he D osophila o holog, O b2 PLD (He ´ as e al., 2021). The O b2 locus is ano he in e es ing example ha encodes six closely ela ed p o ein iso o ms, o which wo iso o ms named O b2A and O b2B s uc u al change and sel -p opaga ion p ope ies (Majum- da e al., 2012). In he adul b ain o D osophila, he O b2A p o ein is exp essed a a low le el. Howe e , i is e y impo an o he oligo- me iza ion o O b2. In ac , he O b2A o m gene a e oligome s mo e easily han O b2B. Ac ually, a mu a ion in O b2A blocking i s oligo- me iza ion a ec s o he pe sis ence o memo y and he exis ence o an O b2A p ion-like domain is su icien o long- e m memo y o ma ion (Whi e-G indley e al., 2014). These la e p ion-like p o eins a e mRNA-binding ansla ion egu- la o s, which newly ela ed his p o ein wi h he ibo ype code. How- e e , al hough he possibili y o posi ing ha he exis ence o a common p ion code is suppo ed by he concomi ances desc ibed, he e is s ill he p oblem o species wi h low suscep ibili y o in ec ion, which pose a J.R. Coca e al. BioSys ems 210 (2021) 104542 5 challenge o he es ablishmen and implemen a ion o a p ion code heo y. We say his because he disco e y o hese po en ial excep ions o a common p ion code, in which P P C would be always able mis old o an al e na i e iso o m, implies he need o know mo e abou he basic elemen s o his biological code and he e olu iona y al e a ions ha allow ce ain o ganisms o p esen hese low suscep ibili y, as hey may de y he unde s anding o he p ion code o pose excep ions o i . In ac , Vidal e al. (2020) showed ha domes ic dogs a e esis an o in ec ion because o he p esence o aspa ic and gu amic acid a posi ion 163 o hei P P. In any case, despi e hei common ea u es, he eno mous di e ences on amino acid sequences o all hese amyloid o ming p o eins hinde s he de ini ion o molecula de e minan s o amyloid olding making di icul o s ablish he undamen s o he amyloid code (Hech e al., 2004). Gi en ha he common ea u e o amyloids is hei h ee-dimensional s uc u e upon mis olding, likely s uc u al de- e minan s will be de ined as a s a ing poin o deciphe he amyloid code. None heless, he ma e could be s ill mo e complex han we can e en imagine, since i has been shown ha some amyloidogenic p o eins can seques e many o he p o eins wi h essen ial unc ions in hei agg ega e- o ma ion pa hway (Olzscha e al., 2011). The di e en examples we ha e p esen ed suppo he idea o a biological code based on he eplica i e cha ac e in amyloid p o eins. As we ha e seen be o e, hese p o eins ha e he capaci y o change o make copies o hemsel es and o adjus (acco ding o Mau y’s hy- po hesis) o en i onmen al cha ac e is ics. These suppo s also, o some ex en , he possibili y ha , yea s ago, molecules wi h simila cha ac e s o hose now ound in species such as Aplysia, Podospo a, among o he s, could ha e exis ed. 5. P ionic neu al code In o de o unde s and p ion eplica ion, P usine (1982) p oposed wha is called he “p o ein only” hypo hesis. This app oach conside ed o he i s ime ha TSE could be caused exclusi ely by mis olding o P P C in o P P Sc , in he absence o nucleic acids ha could explain he ansmission o in o ma ion esul ing in a neu odegene a i e pa hology. In he ligh o his heo y, unde s anding he s uc u e o P P C and i s con e sion o P P Sc is pa icula ly impo an o de ine he biological code ha unde lies he pa hological p ocess ini ia ed by his p o ein. P P C p esen s wo clea ly dis inc egions, he N- e minal po ion o he p ion p o ein is uns uc u ed, and i consis s o a long and lexible ail. On he o he side, he C- e minal domain, also known as he glob- ula domain, con ains h ee α -helices and a sho , wo-s and β-plea ed shee (Mabbo , 2017). Mo eo e , his p o ein is exp essed mos abun- dan ly in he ou e memb ane o ne ous cells whe e i is bound h ough a glycosylphospha idylinosi ol (GPI) ancho . GPI has a majo ele ance in cell signalling ansduc ion and ini ia ing di e en gene exp ession cascades in esponse o ex e nal s imuli and in ac , in p ion diseases, GPI-ancho ed P P C is hough o media e p ion caused neu o oxici y, while his moie y is no essen ial o P P C mis olding and con e sion in o he sel - eplica i e, in ec ious iso o m P P Sc (P iola, 2018). The mis olding e en by which he globula domain o P P C is con- e ed in o a β-shee - ich iso o m is comple ely unknown a a molecula le el bu his new s uc u e shows neu o oxici y, ela i e esis ance o p o einase diges ion, and is accumula es in a ec ed issues in he o m o insoluble agg ega es. The exac h ee-dimensional s uc u e o P P Sc has been long sough , since i s s uc u e encodes he biological p ope ies acqui ed by p ions and is he pa o his semio ic code ha needs o be un a eled in o de o deciphe he in o ma ion ansmission mechanism o code unde lying p ion diso de s. Fo una ely, he i s high- esolu ion h ee-dimensional s uc u e o a mammalian p ion has been ecen ly published, showing a pa allel in- egis e β-shee s uc u e, and b inging biologis s a s ep close o unde s and his unusual in o ma ion encoding mechanism (K aus e al., 2021). We ha e al eady men ioned ha p ion diseases show ce ain analogy o o he diseases such as Alzheime ’s Disease, Pa kinson’s Disease and Hun ing on, among o he p o ein-mis olding ela ed neu odegene a i e diso de s. They a e neu odegene a i e diso de s in which con o ma- ional change and accumula ion o amyloidogenic p o eins occu s. Mo eo e , i has ecen ly been p o en ha hese p o eins can sel - eplica e in a manne simila o he p ion p o ein and hus, p esen cha ac e is ics o eplica o s. In ac , Tau p o ein, β-amyloid and α -synuclein appea o be capable also o cell- o-cell dissemina ion, and could be conside ed as in ec i e p o eins inside a single o ganism. Mo eo e , sligh ly di e en p o ein con o ma ions causing dis inc dis- ease pheno ypes we e also desc ibed o some o hese diso de s, sug- ges ing he exis ence o s ains as in he case o TSE-causing p ions. And inally, he la es s uc u al da a shows a simila a angemen o TSE causing p ions and o he mis olded p o eins such as Aβ pep ide and α -synuclein K aus e al., (2021), making i e en mo e plausible ha a common code could be sha ed by all hese p o eins. Due o hese simi- la i ies some o he diso de s associa ed wi h mis olded p o eins ha e been conside ed as p ion-like diseases: Alzheime ’s disease, Pa kinson’s disease, F on o empo al demen ia, Amyo ophic la e al scle osis and Hun ing on’s disease, which could all be caused by p ions, a e m ha is being expanded om TSE-causing p ions o a wide amily o p o eins sha ing mechanisms and possibly semio ic codes. Ba bie i (2014) explains ha om Code Biology h ee wo lds can be de ined. Wo ld 1 in which o ganic semiosis ope a es, wi h coding as i s mechanism. Wo ld 2 in which animal semiosis unc ions being i s mechanisms coding and in e p e a ion. And Wo ld 3, in which human semiosis ope a es wi h i s mechanisms o coding, in e p e a ion and language. Acco ding o his desc ip ion, p ions could be unde s ood as biosociological adap o s be ween a pa o he molecula wo ld and ano he pa o he neu al wo ld, and also be ween Wo ld 1 and Wo ld 3, since as i has p e iously discussed, p ions ha e simila cha ac e is ics o codemake s. We a e no ad oca ing he exis ence o a uni e sal amyloid code ha can explain he ela ionship be ween hese wo lds. Wha we in end o indica e is ha his p ion code allows us o unde s and di - e en ial elemen s p oduced by TSEs. In ac , he sociological dimension o p ions, seen as adap o s, de i es om he social impac gene a ed by he pa hological e ec s o mis olded P P, wi h de as a ing e ec s in he daily li e o a ec ed people and in hei amilies (Coca e al., 2019). The mani es a ions o he di e en TSEs a e a iable. Some ha e a e y apid de elopmen o neu odegene a ion (3–6 mon hs in humans), while o he s mani es mo e slowly. This, oge he wi h he usually la e diagnos ic, leads o a g ea unce ain y o he closes ela i es. In addi ion, while om he social pe spec i e, some a ec ed people iden- i y p ion diseases (namely C eu z eld-Jakob disease) wi h Alzheime ’s disease (Coca e al., 2019), he e a e speci ic social dis u bances asso- cia ed wi h p ions ha do no a ec o he neu odegene a i e diso de s. Such as he ea o in ec ion which adds a social s igma, and he apidi y o disease p og ession, which o ces he close ela i es o adap con inuously o changing ci cums ances and hinde s he access o social ca e due o long bu eauc a ic p ocesses. This gi es us he idea ha hese diseases also ha e ce ain concomi an s in he social sphe e and ope a e in a simila way in he wo ld h ough a neu odegene a i e p ocess. I is also wo h conside ing, when analysing p ions h ough he scope o biosemio ics, ha one o he main ideas included in he code heo y de eloped by Ba bie i (2003, 2011, 2015, 2019), is ha he e has been a neu al code a he o igin o he conscious mind. Acco ding o his heo y, ha in ends o shed some ligh on he o igin o mind along e olu ion, one o he phases in i s de elopmen was ha named majo ansi ion. As s a ed by Ba bie i (2019), he o igin o he neu al code is a ue bio- logical e olu ion because is a majo ansi ion ha ans o med he unconscious b ain o he ances al animals in o he eeling b ain o he mode n animals (including humans). The esul was he o igin o subjec i i y, he o igin o i s -pe son expe iences, in sho , he o igin o he conscious mind (Ba bie i, 2019). Wi hou going in o u he de ails o he neu al coding heo y, we would like o highligh how he e ec s o con o ma ional al e a ion o P P gene ally b eak his code. J.R. Coca e al. BioSys ems 210 (2021) 104542 6 Going back o he biosociological dimension o he p ion code, Coca e al. (2019) showed in a social s udy ha he apid cou se o he neu- odegene a ion ha leads o he dea h o hose a ec ed, o ces a apid accep ance o he consequences o he disease. Howe e , he e is a ce ain lack o biomedical knowledge which limi s he possibili ies o in o ma ion o he amilies, a ec ing o an e ec i e social and heal h ca e. Fu he mo e, he biological p ocess o he disease caused by he mis olding o P P leads o a b eak in he neu al code, esul ing in neu- odegene a ion which in u n, causes a social dis u bance, no only o hose a ec ed by he disease, bu also o hei closes ela i es. Resea ch on his disease, om he pe spec i e o code biology, has g ea epis emological i ues since i allows us o dig deepe in o he knowledge o he pa hology om a biosocial pe spec i e. In his sense, i is wo h emembe ing ha hese diseases al e codes ha go beyond he me ely biological. Fo his eason, we belie e ha he app oach p o- posed he ein, ha in ends o analyze p ions om a biosemio ics pe spec i e, opens he doo o inc ease ou unde s anding o hese de as a ing diso de s om a esh iewpoin . 6. Conclusion In his a icle we ha e made an app oach o he biology o he p ion code. Thanks o i , we ha e seen ha his code is no limi ed o p ion diseases. In ac , i has been shown ha he e a e simila i ies in di e en p o eins (called amyloids) ha allow us o sugges he exis ence o a common biological code be ween hem. Ob iously, his code canno be he same as he gene ic code, since he ela ed p o eins ha e “in ec i e” capaci y and al e o he p o eins by mis olding hem. Del ing in o his p ion biological code is impo an o unde s and he al e a ions ha hese p o eins gene a e in o ganisms such as humans. We know ha p ion diseases a e neu odegene a i e diseases, bu a be e unde s anding o he biological code could help us o be e un- de s and he biosocial e ec s o his ype o disease. 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