Resumen de Molecular clues to pathogenesis in prion diseases
The infectious age nt of the transmissibl e spongiform encephalopathies (TSE) resembles a virus in that it propagates in vivo a nd has distinct str ai ns.
However, compelling evidence strongly suggests that a posttranslational structura l alteration in a glycoprotein PrPC (the normal, cellular isoform of the so-call ed prion protein) is responsible for pathogenesis of these diseases.
Accordi ng to this hypoth esis - now c lose to being ge nera ll y accepted -, iatroge n, sporad ic and familial forms of TSE would h ave th e sa me mo lec ul ar mechanism: th e conversion of PrPC into a pro teaseresista nt iso fo rm PrPSc kinetically behaves as an autocatalyt ic process which, combined with the hig h turnove r rate of the norma l isofo rm , ma y e ndow the system with bistability propert ies a nd s ub sequ e nt threshold behavior between no rm a l a nd pa thoge ni c stea d y -sta tes. Normal pri o n protein see ms to be necessa ry for lo ng- ter m s urvi va l of Purkinj e neurons, regul at ion of circadian rh ythms a nd , more controversially, for norma l sy naptic functio n. At least part of the pathology might be due to the unavailability of no rmal isoform rather th an to the accumulation of PrPSc. NMR structure of the normal mouse prion protein revea ls a sho rt , unex pected /3-sheet which mig ht be a nuclea tion site for the conformational transition between PrPC and PrPSc. Prion diseases may challenge the edged distinction that we use to make between informational (DNA) a nd functional (proteins) macromolecules.
Pathogenic mechanism of prio ns might also be involved in o th e r pr o te in s to ac hi eve a nd pass o n th e ir co nfo rm a ti o n. He nce, stru c tur a l inh e rit a nce a t the molecular leve l mi g ht be th e missin g link for th e und e rsta nding of th e structur a l inh e rit a n ce processes featured a t th e ce llular leve l. Mo reove r, evo luti o nary paradigm postul atin g a primiti ve RNA wo rld is weakened by th e mec h a nis m of pri o n diseases.
