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The Prion Diseases I _r-.,-.,-.' '.'- -"'. - ~ l,,: ". ft\'OV\-rdf '.ft:e I . 1..., The Prion Diseases , Prions, once dismissedas an impossibility, have now gained I wide recognition as extraordinary agents that cause : a number of infectious, genetic and spontaneousdisorders I by Stanley B.Prusiner 'I Fifteen years ago I evokeda good the brain to becomeriddled with holes. encephalopathy.The last, often called , deal of skepticism when I pro- These ills, which can brew for years (or mad cow disease,is the most worrisome. I.. posed that the infectious agents evenfor decadesin humans)are wide- GeraldA. H. Wells and John W. Wile- I, ' causingcertain degenerativedisorders spreadin animals. smith of the CentralVeterinary labora- I of the central nervous system in ani- The most common form is( scrapie, I tory in Weybridge,England, identified I malsand. more rarely, in humansmight foundin sheepand goats. Afm~t~a:'an: I the conditionin 1986,after it began ! consist of protein and nothing else.At imals lose coordination and eventually striking cows in Great Britain. causing II the time, the notion washeretical. Dog- becomeso incapacitatedthat they can- them to becameuncoordinated and un- ! ma held that the conveyersof transmis- not stand. They also becomeirritable usuallyapprehensive. The sourceof the : sible diseasesrequired geneticmateri- and, in some cases,jeveloP.EI!~e emergingepidemic was soon traced to I al, composedof nucleicacid (DNAor itch that leadsthem to scrapeoff their a food supplementthat indudedmeat I RNA),in order to establishan infection ~~~r hair (hencethe name"scrapie"):- and bone meal from dead sheep.The I in a host. Evenviruses, among the sim- ~otherprton diseasesof anim~ ;1 plest microbes,rely on suchmaterial to by such names as transmissiblemink II direct synthesisof the proteinsneeded encephalopathy,chronic wasting disease for survivaland replication. of mule deer and elk, feline spongiform ~l_I~'11111111 . " Later,many scientistswere similarly encephalopathyand bovinespongiform r,. , dubious when my colleagues and I sug- ...:- gested that these "proteinaceous infec- 40000 >- -.,. ',~ I tious ~artides"-.or "prions," as I called ' ~ ' ~ "; -&fZ;~ the ?is.ease-~ausmgagents-could ~- w Q <"" !! ~. r." .".- ;. , derlie inhented, as well as commuru- (I) 35,000 Q A . ~. ' I cable,diseases. Such d~al b~vior was lli ~'~ ~ ,-*' . then unknown to medical saence, And B 30,000 ~'~ we met resistanceagain when we con- s: 0 .~ i, ODS")cluded multiply that prions in (pronouncedan incredible"pree- way; 8~ 2 5,00 0 ~ - they convert normal protein molecules ~ ~ into dangerousones simply by induc- ~ 20,000 ~ ing the benign molecules to change ~ rr: theirToday, shape. however, a wealth of experi- ~ 15' 000 ~ mental and clinical data has made a ~ ::?. convincing case that we are correct on ~ 10,000 all three counts. Prionsare indeed re- ~ I I t. f;.t . I sponsiblefor trans---missibleand iDfierit- 8 5,000 ~ ~ : : Theye~ Qlsoraers caii (fIs-o of cause pro{em sporaffic conformartou.ffisease, ~ ~:g . ~ ~~ch neither.tran~missio~ ber:"'een ~ ~ ~ ~ ffi' 9?-rJ1' & ~ \,.' , mdiVIduals nor inhentance IS eVIdent. .?5 .?5 .?5 .?5 .'::J ,5?:J.'::J .'::J .'::J : ,",'. '.-,..~.. Moreover, there are hints that the prions SOURCE:John W Wilesmith . , ..: causingthe diseasesexplored thus far . ~ may not be the only ones.Prions made CATn.EWERE INCINERATED to prevent of rather different proteins may con- them" fro.m ~preading ~mad cow. dis- . tribute to other neurodegenerativedis- ease, This disorder,whi~ hasafflict~d eases that are quite prevalent in hu- ~°re. than 130,.000cattle m Grea~Bnt- . am smcethe nud-1980s(graph),ls one !11ans,They nught even partiapate m of several fatal neurodegenerativedis- illnessesthat att~ckm~scles. easesof animals and humansthought The kno~ pnon diseases, all fat~, to be caused by prions-infectious pro- ~ . ar~ sometimes referred to as spongl- teins. Studies are assessingwhether pli- 's: (orm encephalopatrues. They are so on disease can be ttansmined from cows Q. ; ..I named because they 1requently cause to people through the ingestion of beef" ~~.. CAN january 1995 ~ .~ I:" I . methods for processing sheep carcass- Creutzfeldt-Jakob disease,in contrast, . es had been changed in the late 1970s. occurs worldwide and usually becomes STANLEYB. PRUSINERis professorof Where once they would have eliminat- evident as dementia. Most of the time neurologyand bio:chemistryat the Uni- ., ed the scrapie agent in the supplement, it appears sporadically, sttiking one per- versity of Califo~ Schoolof Medidne, . ... .' San Frandsco. He IS a member of the \ now they apparently did not. The Bnt- son m a million, typiCally around age 60. NationalAcademy of Sciencesthe Insti- '-' . ish government banned the use of ani- About 10 to 15 percent of cases are in- rote of Medidne and the 'American ;~ mal-derived feed supplements in 1988, herited, and a small number are, sadly, Academy of Arts and Sciences. He has ~ and the epidemic has probably peaked. iatrogenic-spread inadvertently by the won many awardsfor his researchinto Nevertheless, many people continue to attempt to treat some other medical pri~ns, m~st recently the Albert Lasker 1 wony that they will eventUally fall ill as a problem. Iatrogenic Creutzfeldt- Jakob Basic Me~lcal Research.A":"af~ and the result of having consumed tainted meat. disease has apparently been transmit- Pa~ Ehrlich .Aw~. This. IS his second The human prion diseases are more ted by corneal transplantation, implan- artIcle for SCIentificAmencan. obscure.Kuru has been seen only among tation of dura mater or electrodes in the the Fore highlanders of PapuaNew Guin- brain, use of contaminated surgical in- ea. They call it the "laughing death." struments, and iI\iection of growth hor- Rossella Medori of the University of B0- o Vincent Zigas of the Australian Public mone derived from human pituitaries logna and Pierluigi Gambetti of Case Health Service and D. Carleton Gajdusek (before recombinant growth hormone Western Reserve University. of the U.S. Nati~titutes of Health became available). described it in~oting that many The two remaining human disorders In Search of the Cause highlanders became afflicted with a are Gerstmann-Striiussler-Scheinker dis- " strange, fatal disease marked by loss of ease (which is manifest as ataxia and I first became intrigued by the prion I coordinati~n (ataxia) and ?ft~. later other signs of dama~~ t~ the ce~eb~l- . diseases in 1972, when as a resident " by dementia. The affected mdiVlduals lum) and fatal familial msomma (m m neurology at the University of Cali- probably acquired kuru through ritual which dementia follows difficulty sleep- forma School of Medidne at San Fran- . cannibalism: the Fore tribe reportedly ing). Both these conditions are usually dsco, I lost a patient to Creutzfeldt-Ja- '" honored the dead by eating their brains. inherited and typically appear in mid- kob disease. As I reviewed the scientific ,Ji The practice has since stopped, and life. Fatal familial insomnia was discov- literature on that and related conditions . kuru has virtually disappeared ered only recently, by Elio Lugaresi and I learned that scrapie, Creutzfeldt-Jakob ~ .. r i' I ffi ' I .. " ~. .I..: - ,.,:y:- ~i.~ "'" 1 .,'* - >..- "'" "" .. , SCIENTIFlCAMERICAN january 1995 49 I \ "~~;..t;;;;,~,;\,-~-- rl diseaseand kuru had all beenshown to I immediately began trying to solve duresthat denature(unfold) or degrade be transmissible'.--b in °ec . extracts0 this mystery when I set up a laboratory protein reducedinfectivity. I thus intro- <> seased brains into the brains 0 at U.C.S.F.in 1974.The first step had to duced the term "prion" to distinguish !,~ ~ animals..The infections were be a mechanicalone-purifying the in- this classof diseaseconveyer from vi- i - thought to be causedby a slow-acting fectious material in scrapie-infected ruses,bacteria, fungi and other known , virus, yet no one had managedto iso- brains so that its compositioncould be pathogens.Not long afterward,we de- late the culprit. analyzed.The task wasdaunting; many termined that scrapieprions Cj~d In the courseof reading,I cameacross investigatorshad tried and failed in the a single protein that we calle~~r I an astonishingreport in which Tikvah past. But with the optimism of youth, I "prion proteiIL" I Alper and her colleaguesat the Ham- forg~g_ah~ad(see"Prions;"by-Stanl~ Now the major questionbecame, mersmith Hospital in London suggest- ;-Prusiner;SCIENTIFIC AMERICAN, Octo- ~ere did the instructions specifying ed that the scrapie agent might lack ber 1984 . B-.".--1982my COlleal!Ues-4nd=F-111'esequence of amino acids in PrPre- I I nucleic aCId;wrucn usually can be de- progress,producing ex- side?Were they carriedby an undetect- grnaed by ultraVioletor ionizing ractia:- tracts of hamster brains consistingal- ed pieceof DNA that traveledwith PrP, tion. wilen me nucleicacid in extracts~ most exclusivelyof infectiousmaterial. or were they, perhaps,contained in a oficrapie-infected brains was presurn- We had, furthermore,subjected the ex- gene housed in the chromosomesof ably destroyedby thosetreatments, the tracts to a range of tests designedto cells? The key to this riddle was the I extracts retained their ability to trans- reveal the composition of the disease- identification in 1984 of some 15 arni- i mit scrapie. If the or~anism did lac~ causingcomponent. -no aCl~at one ena or me YrYprotein: i ; DNA and RNA.the finding would mean ~ group iaentified this short amino I I tlmt~ not a virus or any other- AmazingDiscovery acid sequencein collaborationwith
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