“Fondation Marcel Merieux” International symposium on PRION DISEASES AND RELA ED PRO!

ESSES "Annecy France #$%#& No'em(er $)))*
Poster "or Oral* Session Proposal

”From PRIONS and PRIONS%LI+E IN,ARIAN S to t-e SELF%ASSEM.L/ 0ESIS”
Jean-claude PEREZ Scientific Director genum 7 Avenue de Terre-rouge F33127 Martigna tel ! 33-"##$7%$23$ Fa& ! 33-"##$21'2"3 e-(ail ! )c*ere+13',aol-co( ...-genu(-co(

A.S RA! 1
Funda(ental re earc/ not 0et *u1li /ed ena1le u to unif02 overall2 t/e geno(ic and *roteo(ic infor(ation of an0 genetic e3uence- T/i funda(ental la. i 1a ed on a 1io-(at/e(atic unification of all genetic infor(ation 41ioato( 2 nucleotide 2 codon 2 a(ino acid 2 D5A6R5A6Protein 7 fro( t/e level of t/e i& 1a ic 1io-ato( 8 9 5 : S P to t/e glo1al level of ./ole geno(e T/i la.2 ./ic/ .e na(e "UNIVERSALIS GENETIC CODES: Global Unified Genetic Codes (GUGC "2 traduce a glo1al genetic tuning and 1alancing unif0ing an0 D5A e3uence and it e3uivalent tran lated into a(ino acid A an indication2 one (ea ure a linear ;E59M<8S6PR9TE9M<8S cou*ling of =7> for t/e ./ole geno(e of A<DS :<?1-:@A22 lengt/ of (ore t/an =""" 1*2 including a1out ten gene and en+0(e 8oncretel02 t/e d0na(ic of t/i ;E59M<8S6PR9TE9M<8S cou*ling i a**eared a t.o correlated curve tran lating to*olog0 and t/e d0na(ic evolution of a /ierarc/ical cla ification of codon t/roug/out t/e tudied e3uenceMore *reci el02 t/e tud0 of t/e e curve /o. t/at t/i tool /ig/lig/t t/e functional area and active ite .it/in *rotein T/e *ecific conte&t of PR<95S area could 1e an intere ting field to run and i(*rove our ne. 1a ic re earc/ a**roac/Stud0ing PR<95S 10 t/i (et/od underline t.o re(arBa1le fact ! - A 3ua i-*erfect cou*ling 1et.een ;E59M<8S and PR9TE9M<8S e3uence 4a1out =$ to =%> for t/e (o t co((on PR<95S7- T.o concurrent2 di tant ite of a**ro&i(atel0 '" a(ino acid 2 are underlined- Ce t/oug/t t/at t/e e t.o concurrent ite could con titute t.o D functional attrator D ./ic/ could 1e at t/e origin of t/e t.o ta1le tructure PrPc and PrP c of Prion PRION Genomics/Proteomics Global Link
r=96.8% and evidence of 2 "attractors"

C o d o n s h i e r a r c h i c a l c l a s s i fi c a t i o n

300 250 200 150 100 50 0 Codons/Amino acids se !ential "ositions #enomics $%A codons &roteomics A.A.

Ce t/u

oug/t to te t2 i(ulate and validate t/i t/e i according to t/e four follo.ing *rotocol of e&*eri(ent !

#2 3ni4ication o4 t-e #&5 PRIONS o4 6en.an7  -i8-li8-tin8 o4 an IN,ARIAN 1
Ce anal0+ed 0 te(aticall0 AEE ;enAanB A?A<EAAEE PR<95S and PR<95S-E<FE- T/e econd of t/e t.o ite *re ented a1ove 4Ma)or ite to.ard codon 13% in /u(an Prion7 a**ear in t/e (a)orit0 ;enAanB PR<95S in t/e for( of an o*ti(u( con en u centered on t/e area 9rpIi-48s92 T/i G5<F<8AT<95 i ver0 1e0ond t/e D 1arrier of t/e *ecie D2 t/e lengt/ of Prion tudied and even of t/e *reci e value of eac/ a(ino acid - For infor(ation2 (ore t/an %3> of t/e 1$7 Prion tudied i unified on t/i D *attern D- <n ot/er /and 2 (ore t/an 3 Prion 10 ' /ave a ;E59M<8S6PR9TE9M<8S cou*ling /ig/er t/an =#>-

$2 -esis o4 sel4%assem(lies PRION PRION or PRION  Scrapie 4ollo:in8 a s-i4t around ;) codons1
Ce i(agined variou cenario of interaction PR<95S  PR<95S articulated around t/e e 2 ite - 9ne of t/e( lead to a PERFE8T 89GPE<5; of dou1le interaction D5A6D5A train and PR9TE9M<8S6PR9TE9M<8S train - T/ere i a1out a elf-a e(1l0 1et.een 1ot/ Prion *rotein .it/ a relative /ifting 10 a**ro&i(atel0 '" codon 4./ic/ con titute al o t/e a(ino acid di tance 1et.een t/e 2 ite 7- Ce te t t/e e /01rid a e(1lie for t/e (an2 t/e co.2 t/e /ee*2 t/e (ou e and t/e ra11it9ne di tingui /e 2 ca e PR<95  PR<95 and PR<95  Scra*ie 4;olden :a( ter7- Gnification ;E59M<8S6PR9TE9M<8S i al.a0 H=2> on average- T/i *o i1le interaction i D a1ove D t/e conce*t of *ecie T/e o*ti(al /ift varie fro( 37 to '" codon according to *ecie -

<2 ,alidation o4 our t-esis on 'arious experiments lin7ed :it- pat-o8enicity "s-eep= -uman !>D= ? PR3SINER miniprions ?= etc9*1
T/en2 .e run our t/e i on e&*eri(ental *u1li /ed ca e connecting c/ange and *at/ogenicit0 of Prion - T/u 2 .e /o. t/at t/e 3ualit0 of t/e ;eno(ic 6Proteo(ic cou*ling for t/e '" codon /ift 1a ed elf-a e(1l0 (ove in t/e a(e direction a t/e /ee* *at/ogenicit0 4(utation et ?RI2 AR:2 ARI2 ARR and A:I7- <n t/e a(e .a02 .e a ociate cou*ling ;E59M<8S6PR9TE9M<8S and *at/ogenicit0 for t/e (an 4c/ange 1"22 12=617% and ;SS6FF<68JD7- Ea tl02 our (odel co(*letel0 confir( t/e e&*eri(ent of Profe or Stanle0 PRGS<5ER on t/e D MiniPrion D-

;2 Extension o4 our assumption to t-e 4ield o4 t-e ? PRIONS%LI+E ? "3RE<= S3P<@P yeast and -omolo8ues*1 8an t/e <nvariant and elf-a e(1l0 t/e i 1e .ide until t/e related field of D Prion -EiBe DJ
T/en2 .e tudied GRE3! it a**ear a *attern i(ilar to Prion one 4dou1le attractor 72 (oreover .e di cover 3uicBl0 a *o i1le elf-a e(1l0 GRE3  GRE3 4o*ti(al /ift of 1# codon and cou*ling rK=1-7>7- <n t/e a(e .a0 a generali+ation i running on SGP3# 0ea t and /o(ologue - For e&a(*le2 in t/e Dro o*/ila a(*le 4;enAanB! G%%%$%72 D u*3# Prion-liBe *roduce a d0na(ic of ;eno(ic 6Proteo(ic curve i(ilar to t/e a1ove regular Prion curve - A elf-a e(1l0 /ift t/e i i al o *ro*o ed-

PERSPE! I,ES1 <t i a D ne. *oint of vie. D of t/e PR<95S F<EED ./ic/ are *ro*o ed /ere- Ae0ond a
u**ort D Aio-Mat/e(atic D2 .e G5<FL infor(ation ;E59M<8S6PR9TE9M<8S of all t/e( Prion - Ce *ro*o e and validate a t/e i 2 *lau i1le2 of elf-interaction 1et.een Prion - T/i (odel i 1e0ond and a*art fro( t/e D 1arrier of t/e *ecie D9ur t/e i ee( confir(ed 10 (ulti*le e&*eri(ent *u1li /ed2 it .ould ee( trongl0 a ociated .it/ t/e *at/ogenicit0- Ea tl02 our (odel of interaction PR<95  PR<95 ee( to e&tend to t/e D PR<95S-E<FE DMand even to ot/er *e*tide ! .e validated it2 t/erefore2 on t/e for(ation of AMLE9<DS *la3ue 4Aeta A' A(0loid AEZ:E<MER2 *articularl0 *e*tide A-1eta 1-'27-

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