Artigo 17 - Prion-Like Transmission of Protein Aggregates in Neurodegenerative Diseases

8/6/2019 Artigo 17 - Prion-Like Transmission of Protein Aggregates in Neurodegenerative Diseases

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The depositio of aggegated poteis adbiqiti ito itacellla iclsio bodiesis a commo eopathological deomiatofo most eodegeeatie disodes, icldig Pakisos, Alzheimes ad Htigtosdiseases, as well as tasmissible pioecephalopathies. Each disode is chaacteized by the misfoldig of a specific potei opoteis: syclei i Pakisos disease,amyloid ad ta i Alzheimes disease,htigti i Htigtos disease adpio potei (PP) i tasmissible pioecephalopathies. This sggests that impaiedpotei homeostasis is a shaed pathogeicfeate of these othewise cliically adetiologically diese diseases.

Potei misfoldig ca eslt fom atie

poteis chagig thei cofomatios oewly sythesized polypeptides failig to foldpopely(FIG. 1). Icompletely o icoectlyfolded poteis expose hydophobic amioacid side chais o thei sfaces that aeomally bied i the iteio of the atiestate. Ths, they become poe to selfassociatio ito aggegates that ca fctioas clei that ecit additioal moomes(FIG. 1; BOX 1). Sch potei aggegates cabecome ifectios ad ae called pios1,2if the itemolecla iteactios betweethe costittie molecles ae so stog that

aggegatio is effectiely ieesible, if theyesist the cell cleaace machiey(BOX 2)ad if they popagate fom oe cell to aothe(FIG. 2), i which they ecit oatiepolypeptide moomes. Mammalia PPis a plasma membae potei1, wheeassyclei, htigti ad ta ae omallycytosolic. Ths, the popagatio ad tasmissio of syclei, htigti ad taaggegates pobably diffe fom PP. Thegeeic molecla basis of pio paticlefomatio ad tasmissio is illstated iBOX 1. Potei ifectiity depeds o seealfactos: ieesibility of oatie poteiassemblies, the efficiecy by which pecsopolypeptides ae ecited ito aggegates, theesistace of aggegates to the cellla clea

ace machiey ad the efficiecy with whichaggegates ca tasfe to eighboig cells.

I this Opiio aticle we highlighthow the eopathologies of Pakisos,Alzheimes ad Htigtos diseasesdeelop oe time ad space, ad descibeecet fidigs sppotig the idea thatpathogeic poteis ca tasfe betweecells. We popose that itecellla poteitasfe cotibtes to the pogessioof eodegeeatie diseases ad,theefoe, ca costitte a taget fofte diseasemodifyig theapies.

Patters f eurpathlgy spread

I eodegeeatie diseases, sch asPakisos, Alzheimes ad Htigtosdiseases, pathological chages typicallydeelop i the eos system followig specific aatomical pattes that ae chaacteistic fo each disode (FIG. 3). These pattesidicate that the pathology is ot oly simplypopagated betwee eighboig cell bodies,bt that it also speads alog axoal pathwayseithe away fom (ateogadely) o towads(etogadely) the cell body(FIG. 3a).

Parkinsons disease.The eopathologicalhallmaks of the moemet disodePakisos disease ae Lewy bodies ad Lewyeites, which ae potei aggegates i thecell body ad eoal pocesses, espectiely.The most abdat potei i the aggegatesis syclei. This 140 amio acid pesyaptic potei is atiely folded (that is,it lacks a welldefied stable tetiay stctewhe isolated), iteacts with mltiple poteis as well as lipids ad membaes, adhas bee sggested to play a pat i esiclataspot3. Althogh most Pakisos diseasecases ae idiopathic (of a kow case),mtatios i the syclei gee delieae, iheited foms.

Baak ad cowokes hypothesized thatbaistem ad ateio olfactoy stctesae afflicted by syclei aggegates eyealy i Pakisos disease4. Ideed, thesechages ae sggested to occ seeal yeasbefoe iolemet of the sbstatia iga the midbai egio, the degeeatioof which is associated with moto dysfctio i Pakisos disease4,5. Sycleiaggegates ae sggested to pogess i atopogaphically pedictable mae as the

pathology speads thogh aatomical coectios thoghot the baistem, limbicad atoomic systems ad eocotex 4,5(FIG. 3b). Baak ad cowokes poposethat this spead pimaily follows pathwayscosistig of log myeliated axos adthat it stats i the olfactoy system ad gt 6.Olfactoy dysfctio is ow cosideeda ealy sig of Pakisos disease adi adaced disease people ofte exhibitdemetia, depessio ad atoomic eos system dysfctio, possibly owig tothe speadig of syclei aggegates6.

o P i n i o n

Prion-like transmission of proteinaggregates in neurodegenerativediseases

Patrik Brundin, Ronald Melki and Ron Kopito

Abtrat | Nurodgnrat da ar ommonly aoatd wth th

aumulaton of ntrallular or xtrallular protn aggrgat. Rnt tuduggt that th aggrgat ar apabl of rong llular mmbran and an

drtly ontrbut to th propagaton of nurodgnrat da pathogn.

W propo that, on ntatd, nuropathologal hang mght prad n a

pron-lk mannr and that da progron aoatd wth th ntrllular

tranfr of pathogn protn. Th tranfr of nakd nftou partl btwn

ll ould thrfor b a targt for nw da-modfyng thrap.

PeRsPecTives

nATurE rEvIEWS |Molecular cell Biology vOLuME 11 | APrIL 2010 |301

20 Macmillan Publishers Limited. All rights reserved10
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=168600http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=168600


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Unfoldedpolypeptide

Foldingintermediate

Nativepolypeptide

Folding

FoldingUnfolding

Slow Slow

Fast

Unstablenon-nativeoligomer

Unstablenon-nativeoligomer

Stable non-nativeoligomer(aggregation nucleus)

Non-nativemonomer(foldingintermediate)

Non-native monomeraddition

Stableoligomergrowth

Stable oligomer breakage

Increased number ofaggregation nuclei

Althogh the cocept of Baaks eopathological stages has gaied mch attetio7,8, itis ot aimosly sppoted. Fo example,diffeet bai egios hae bee sggestedto ay i thei ssceptibility to the kowdelyig disease tigge ad this coldcotibte to the steeotypical patte9,10.Some iestigatos hae also qestioedthe epodcibility of the patte betweepatiets ad state that it does ot always follow the same tempoal ode o aatomicaldistibtio9,10.

Alzheimers disease.Alzheimes disease ischaacteized by the loss of eos adsyapses i the ceebal cotex ad cetai

sbcotical egios. neofibillay taglesad amyloid plaqes ae the classical eopathological hallmaks of Alzheimesdisease11,12. neofibillay tagles aecytoplasmic iclsio bodies that aeich i a hypephosphoylated fom ofthe micotbleassociated potei ta13.nomally, ta, which is a atiely foldedpotei like syclei, is a solble poteithat iteacts with tbli to stabilize micotbles ad pomote micotble assemblyi the bai. Hypephosphoylated ta tedsto aggegate to fom itacellla tagles

of paied helical ad staight filamets.Amyloid plaqes, howee, ae extacelllaad ae pimaily made p of isolbleaggegates of amyloid a 3943 esidepoteolytic cleaage podct of amyloid pecso potei (APP), which is a tasmembae potei of kow fctio14. Mostcases of Alzheimes disease, like Pakisosdisease, ae idiopathic, althogh mtatiosi the gee ecodig APP o i the ezymesthat seqetially cleae it case iheitedfoms of Alzheimes disease14.

I Alzheimes disease, eofibillaytagles pogessiely spead thoghot thebai i a aatomically steeotypical mae. Some of the fist egios affected by

tagles, possibly peceded by olfactoy aeas15,ae the hippocamps (ad closely associatedstctes), the basal cles of Meyet adthe baistem, wheeas the eocotex is otioled til the disease is moe adaced(FIG. 3c)16,17. Ee i the hippocamps adelated stctes, the deelopmet of tapathology has bee sggested to follow coectios ateogadely18. By cotast, thespeadig of amyloid pathology does otpogess thogh sch a aatomically stictpatte i Alzheimes disease ad coelatespooly with the leel of cogitie declie11,19.

Huntingtons disease.Mtatios i the geeecodig htigti delie the atosomaldomiat iheitace of Htigtosdisease, which is chaacteized by ioltay moemets, pesoality chages addemetia. Htigti is made p of 3,144amio acids, is expessed widely thoghotthe body ad has meos iteactig potei pates. Its omal fctios ae otflly destood; it has bee implicated iatiapoptosis, eoal gee tasciptio,syaptic fctio ad esicle ad axoaltaspot20. Expasio of a CAG epeati exo 1of the htigti gee aboe acitical theshold of 3540 CAG epeatscases Htigtos disease. The mtatioecodes a expaded polygltamie tactwhich makes the potei (o a fagmetof the potei) poe to aggegate ad tofom itaeoal iclsio bodies21,22.Htigti fagmets beaig fewe tha

35 gltamies do ot aggegate ad fagmets with moe tha 40 aggegate eadily23.The loge the polygltamie tact, themoe apid the aggegatio23 ad the ealiethe disease oset24, showig that htigtiaggegatio is itimately liked to diseasepathogeesis.

Classical desciptios of Htigtosdisease emphasize that degeeatio simltaeosly pogesses i two defied aatomicaldiectios i the stiatm25. Stiatal pojectio eos, paticlaly those expessigecephali, ae amog the fist affected iHtigtos disease26. Bai imagig stdieseeal that the basal gaglia ae shkeee befoe symptoms iolig ioltaymoemets emege27. recet bai imagigstdies, howee, show that aios coticalegios ioled i moto, sesoy ad

isal fctios aleady dego thiig iasymptomatic htigti gee caies, adcotical aeas that sbsee moe adacedbai fctios ae afflicted late 28. Ths,cotical degeeatio i Htigtos diseasefollows a topogaphically pedictable patte.Take togethe, degeeatie pheomeafollow distict pattes i Htigtos

disease, ee if the pecise tempoal adtopogaphical maps of degeeatio ae stillot well established (FIG. 3d).

Pr-lke aggregate trasmss

Seeal ecet expeimetal fidigs adcliical obseatios hae sggested that potei aggegates associated with Pakisos,Alzheimes ad Htigtos diseases, mightmoe fom affected to affected aeas of thebai, sggestig that piolike tasmissioof these diseases cotibte to the aatomicalspead of disease pathology.

Fgur 1 | B mm p . Th foldng of nwly ynthzd polypptd

han nto thr nat onformaton and th unfoldng of protn from thr nat tat prod

through dtnt ntrmdat. som of th ntrmdat ar abl to lf-aoat to form non-

nat olgomr p of dffrnt z and trutur, n whh a gn molul ntrat through

two ntrfa wth two nghbourng molul (an ntrmdat n whh longtudnal ntraton

ar tablhd hown). A th polypptd nold n pron, Parknon, Alzhmr and

Huntngton da populat a wd arty of foldng ntrmdat, thy ha a hghr propntyto form uh olgomr p. Th tablty of th olgomr nra on tablhmnt of up-

plmntary ntrmolular ntraton wth non-nat polypptd through addtonal ntrfa,

a a gn molul n th olgomr bom multalnt. Th rat-lmtng tp n non-nat polypp-

td aggrgaton thrfor th formaton of tabl olgomr. suh olgomr bha a nul and

grow from thr nd by rrutng non-nat monomr. A th bndng of a molul to th olgomr

gnrat an norporaton t for anothr ubunt, th growth of th tabl nul unlmtd.

Brownan52 momnt and rng and/or daggrgatng fator gnrat nrad numbr of nd

and nra th lklhood of nw ubunt bng norporatd.

P e r s P e c t i v e s

302 | APrIL 2010 | vOLuME 11 www..m/w/mb



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12

3

4

5

6

6

7

8

Abnormal prion

Native prion

Unstable prionoligomer

66

Stable prionaggregate(nucleus)

Nucleation Elongation

Steady state

Steady state

Elongation

Fra

ction

aggregated

Time

a Prion aggregation b Prion spread from cell to cell

c Cooperative aggregation of prion andprion-like proteins

3

1

2

Prion aggregate

Nanotube

Native prion Dendrite

Axon

4

Grafted cells develop Lewy bodies.A seiesof atopsies of Pakisos disease patietswho had eceied tasplats of healthyembyoic eos oe oe decade ealiehae poided oel isight ito mechaisms that might delie the pogessioof Pakisos disease pathology29. A sbset (25% oe 5 yeas) of the gaftedeos displayed aggegates cotaiigsyclei2933. These iclsio bodieswee positie fo all the classical makes ofLewy bodies ad exhibited potei fibilsat the ltastctal leel. Stdies oPakisos disease patiets dyig sooe(15 yeas) afte tasplat sgey did oteeal ay potei aggegates i the gaftedeos, showig that Lewy bodies deelopslowly o with a log delay i peioslyhealthy embyoic eos29,30. These datasggest that the Pakisoia bai pomotes coesio of solble syclei

ito a isolble fom, bt do ot eealthe ate of the aget of this coesio.recetly, mose eal stem cells taggedwith gee floescet potei (GFP) weeepoted to deelop itacellla sycleiimmoeactiity ad occasioalsycleipositie iclsio bodies wheijected ito the hippocamps of tasgeicmice expessig hma syclei34.These stdies sggest that hostdeiedsyclei ca ete tasplated ealcells, aalogos to the fidigs i gaftedPakisos disease patiets.

Syclei is itealized by cellsin vitro. Additioal sppot fo the hypothesis that syclei ca moe betweeeos has come fom in vitro stdiesi which GFPlabelled eal stem cells34o SHSY5Y cells (a dopamiegic celllie)35 wee clted togethe with pesyclei. Afte 2448 hs of icbatio,the added syclei, maked with a floescet tag, cold be see i the cytoplasmof the cells. Syclei cold also be seei GFPlabelled eal stem cells that weeclted togethe with eoal cells oeexpessig hma syclei, sggestig

that syclei is tasfeed betwee cellsi clte34,35. Aothe stdy epots thatGFPtagged syclei oligomes addedto clte media ca be itealized by pimay cotical eos egieeed to expesssyclei tagged with ed floescetpotei36,37. Moeoe, the additio of extacellla GFPsyclei idced the fomatio of iclsio bodies i the cytoplasmof the ecipiet cells that wee labelled withboth floophoes, sggestig that the itealized potei ca act as a seed to ecitedogeos syclei ito aggegates34,36,37.

Take togethe, eslts fom hmaatopsies, cell cltes ad tasgeic micesggest that itecellla syclei tasfeca cotibte to the speadig of eopathology i Pakisos disease, whichcold explai why the pathology pogessessteeotypically i accodace with the stagesdescibed by Baak4. Specifically, oatiefoms of syclei ca migate fom cellto cell alog axoal pathways, leadig topogessie popagatio of cellla pathology ad gadally affectig geate patsof the cetal eos system.

Alzheimers disease and protein seeding.Two seies of expeimets sppot theotio that potei seedig (wheebya misfolded potei acts as a seed thatiitiates aggegate fomatio by ecitig additioal folded o oligomeicspecies of the same potei) cotibtesto the deelopmet of Alzheimes diseaseeopathology. I expeimets o miceoeexpessig APP, ijectios of amyloidextacts deied fom bais of Alzheimesdisease patiets o aged APP tasgeicmice cased the depositio of amyloid38.

Box 1 | Mlecular bass f pr partcle frmat, grwth ad trasmss

Native (sphere) prion molecules undergo conformational changes that lead to an abnormal (cube)

form (see the figure; part , step 1). This event is unfavourable because the abnormal form is either

unstable (part , step 2) or sensitive to clearance. According to the template assistance model,

prions in their abnormal form interact with native prions (part , step 3) and convert them into

the abnormal form (part , step 4). The alternative seeded polymerization model proposes that

abnormal prions have the ability to interact with molecules in a similar state (part , step 5).

The oligomeric species formed are unstable because the intermolecular interactions do not

outweigh the entropic cost of binding. They grow by the incorporation of abnormal prion

molecules (part , step 6) and dissociate (part , step 7) until a stable nucleus is formed. Such a

stable prion aggregate can then grow indefinitely from one or both ends and can also break into

smaller fragments (part , step 8) that act as nuclei (part , step 6).

Prion aggregates bind to native prion molecules or receptor proteins attached to the cell

membrane, and are internalized by endocytosis (part b, step 1). They reach the cytoplasm, byan unknown process, where they grow by the incorporation of cytosolic prions. They can move

along the axon in one direction or another (part b, step 2) and can reach neighbour cells through

axondendrite connections (part b, step 3) and nanotubes (part b, step 4).

Prions and polypeptides involved in Parkinsons, Alzheimers and Huntingtons diseases form

aggregates that resist protein denaturation treatments (see the figure, part ). This process can be

monitored experimentally. Stable oligomer formation is thermodynamically unfavourable and this

is reflected by a nucleation phase. The stable oligomers elongate in an exponential manner until

the soluble protein concentration reaches the critical concentration, above which assembly

occurs. These events give a sigmoidal shape to the assembly kinetic (see the figure, part; green

curve). The nucleation phase is abolished (see the figure, part ; orange curve) when preformed

aggregates that act as seeds are added to the protein solution.





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Unfoldedprotein

Foldingintermediate

Nativeprotein

Degradation

Degradation

Accumulation

Non-nativeprotein oligomer

HSP70 Ubiquitin

26Sproteasome

Phagophore Autop hagosom e Autolysosome

Nucleus

Microtubule

Dynein

Centrosome

a b

c

d

e

+

Impotatly, these expeimets ioledthe extacellla depositio of amyloidad ot tasmembae ptake adseedig, makig them fdametallydiffeet fom the othe models we discss.By cotast, aothe seies of expeimetsexamied the ability of aggegated ta toete cells i clte39. Floescetly taggedaggegates of a ta fagmet wee itealized by C17.2 eal cells ad HEK293cells, eithe whe the pe aggegates weeadded to the clte media o whe the cellswee coclted with cells expessig a

aggegatiopoe ta fagmet39. Thesein vitro expeimets aise the possibilitythat ta, like syclei, ca moe fomoe bai cell to aothe. Oce iside, theaggegated ta cold seed the aggegatioof the edogeos potei39, i aalogyto pio popagatio (BOX 1). This is sppoted by obseatios that mtat hmata ijected ito mose bais idces theaggegatio of the edogeos wildtypemose potei, ad that pathology speadsfom the ijectio site to eighboigbai egios40.

Uptake of huntingtin aggregates.Yag adcolleages fist epoted that lage aggegates composed of f loescetly tagged,sythetic polygltamie peptides ca betake p by clted cells41. Whe thesepeptide aggegates wee appeded with aclea localizatio sigal, they taslocatedto the cles ad became highly toxic,implyig that they had become accessible tocytoplasmic clea impot factos. Moeecetly, it was epoted that whe similapolygltamie aggegates o ecombiatfagmets of mtat htigti wee addedto medim, they wee cocetated i

jxtaclea iclsio bodies i cltedHEK293 cells42. To diectly assess whethethe itealized aggegates had becomeexposed to the cytoplasm, as opposedto emaiig i a esicla o acolacompatmet, a itacellla seedigexpeimet was codcted42. Whe the

ecipiet cells wee egieeed to expessa floescet esio of htigti ecodig 25 gltamies (below the theshold fospotaeos aggegatio), the additio offloescet htigti aggegates cotaiig 44 gltamies to the clte medimalteed the distibtio of the 25gltamieepote fom a diffse to a pctatepatte ad cased it to colocalize withthe exteally added potei. This did otocc whe the htigticotaiigecipiet cells itealized aggegates composed of othe amyloids, idicatig thatthe chages wee pobably de to a seededpolymeizatio pocess ad that some ofthe itealized mateial had gaied accessto the cytoplasm42. remakably, whe cellsthat had bee exposed to polygltamieaggegates wee maitaied i pologedcell clte, the aggegated pheotype ofthe 25gltamie htigti epote pesisted fo oe 80 geeatios, althoghthe factio of cells exhibitig this pheotype emaied low, possibly owig toeqal mitotic segegatio of aggegatesi mammalia cells43. This idicates thatpolygltamie aggegates, like pios, ca

eplicate, pesmably by a seedig cleatio mechaism i which aggegatehtigti seeds ae tasmitted todaghte cells dig cell diisio42.

Cetly, the eleace of theseobseatios to Htigtos diseasepathogeesis is clea. neos gaftedito Htigtos disease patiets baisexhibit poo logtem (> 10 yeas)sial ad hae bee sggested to sstaidamage owig to excitotoxicity o iflammatio, implicatig ocellatoomospathogeetic factos i the disease44.

Box 2 | Cellular defeces agast prte aggregat

Protein folding proceeds through intermediates, which expose hydrophobic amino acid side

chains on their surfaces that are normally buried in the interior of the native state, and are

therefore prone to self-associate into non-native oligomers (see the figure, part). Molecular

chaperones of the heat shock protein 70 (HSP70) family interact transiently with these

aggregation-prone surfaces (see the figure, part b). They either compete with self-association

or favour the formation of native contacts and help maintain intermediates in a monomeric,

folding-competent state. Mutations or polymorphisms can destabilize the native state or decrease

the efficiency of folding. Insufficient amounts of molecular chaperones also affect folding

efficiency. Incompletely folded proteins are tagged with polyubiquitin chains, which direct

them to the 26S proteasome for degradation (see the figure, part ). Molecular chaperones

contribute to this process by maintaining the proteins in a state that can be unfolded by the26S proteasome. Proteins that escape degradation by the 26S proteasome can be degraded

by lysosomes through macroautophagy (see the figure, part ). Autophagic degradation begins

with the capture of the substrate proteins (or aggregates) into phagophores that mature

into autophagosomes a vesicular structure enclosed by two concentric lipid bilayer

membranes. Autophagosomes fuse with organelles of the endosomal and lysosomal pathways to

form autolysosomes that, endowed with acidic pH and lysosomal hydrolases, are able to degrade

proteins without the need to unfold them. Finally, the interaction of protein aggregates with the

minus end-directed microtubule motor cytoplasmic dynein results in their accumulation around

the centrosome or microtubule organizing centre (see the figure, part ). This process may

facilitate the capture of aggregates by macroautophagy or may serve to concentrate potentially

toxic aggregation nuclei in a defined region of the cell.





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Nucleus

Proteinaggregate

Nucleus

Cell death?Passive release(membrane rupture)

Passive uptake(membrane rupture)

Exocytosis

Endocytosis

a Release of protein aggregates

b Uptake of protein aggregates

c Cell-to-cell propagation

Membranereceptor

Phospholipid

?

Nucleus NucleusNanotube

I cotast to the Pakisos disease tasplat stdies, the gafts i Htigtosdisease patiets exhibited o mophological eidece that htigti withexpaded polygltamie had tasfeedfom host to gaft withi a decade. Thesefidigs do ot, howee, peclde a olefo celltocell tasmissio of htigtiaggegates i Htigtos disease pogessio. neotoxicity i Htigtos diseasemight well be de to a combiatio ofexcitotoxic ad iflammatoy damage, adpiolike htigti tasmissio mighthae a ole i the pathogeic cascade,pehaps oecomig the potectie effectsof the machiey descibed i BOX 2.

Hw aggregates mve betwee cells

The spead of potei aggegates i theeos system is likely to cotibte tothe adaces of cliical symptoms ad

eopathological chages i Alzheimes,Pakisos ad Htigtos diseases.recet stdies hae demostated celltocell o mediatocell tasfe of aggegates,bt hae gie less isight ito the mechaisms by which they ae eleased otakep. Below, we descibe potetialdelyig mechaisms.

Requisites for cell-to-cell transmission.I ode fo a piolike mechaism tocotibte to the pogessio of a eodegeeatie disease, fo basic eqiemets mst be flfilled. Fist ad foemost,the potei aggegate mst be capable ofelogatig by the ecitmet of solblepolypeptide chais ad fagmetig togeeate additioal elogatio sites adamplify aggegatio (FIG. 1;BOX 1). This hasow bee established in vitro, istdiesdiscssed aboe, fo poteis species thataggegate i Pakisos disease, taopathyad Htigtos disease. Secod, cellsifected by aggegates mst cotiosly sythesize the oaggegated fom.Thid, the tasmissible aggegate mst beeleased fom cells (FIG. 2a). Foth, agge

gates mst be able to bid ad ete theecipiet cell (FIG. 2b).

Mechanisms of aggregate release. Cellsca elease aggegates eithe by a esiclemediated exocytic pocess, pehaps esltigfom icomplete atophagocytosis45, o bylysosomal exocytosis46(FIG. 2a). Cltedeoblastoma cells ad eos secetesyclei moomes ad aggegates bya oclassical esiclemediated exocyticmechaism; howee, the molecla detailsae still kow47. Alteatiely, aggegates

ca be passiely eleased fom cells eithe obidig ad local pte of the membaeo afte cell lysis, which cold occ as aeslt of the toxicity imposed o cells by thebde of high leels of potei aggegatio(FIG. 2a). Fo example, whe cells expessightigti beaig a expaded polygltamie tact wee selectiely killed, the

eleased aggegates cased cleatio of acytoplasmic polygltamie epote poteiiside coclted cells42. Althogh bothpotetial elease mechaisms (exocytosisad cell pte de to death) ae likely toocc i eodegeeatie disease, theielatie impotace to pathogeesis has otbee stdied.

Fgur 2 | P pw p p b . | Protn

aggrgat formd n ll an b paly rlad from ll by mmbran ruptur or damag,

prhap aompanyng ll dath. Altrnatly, ytoplam aggrgat an b atly rlad

by xoyto, pobly followng aptur by maroautophagy and m-ortng or nomplt dg-

ton n th ndoomal and lyoomal ytm. b | Lkw, protn aggrgat that bnd paly

to ll mmbran omponnt (phopholpd or protn rptor) an ntr th ll thr pa-

ly by phyal ruptur of th plama mmbran or atly through ndoyto. Aggrgat

takn up by ndoyto mut ro a bologal mmbran to rah th ytoplam, whr thy an

longat by norporaton of thr onttutng protn. | Protn aggrgat, thr formd nll or takn up by ll, an alo atly propagat from ll to ll, pobly by ytokltal

omponnt uh a molular motor and nanotub ( alo BOX 1).





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Exocytosis

Releaseat death

Anterogradetransport

Retrograde

transport

Axon

Neuronalcell body

b Parkinsons diseasea Models of spread

d Huntingtons diseasec Alzheimers disease

Mechanisms of aggregate uptake. I cltedcells, itealized syclei aggegatespatially colocalized with edosomalad lysosomal makes35. Expessio ofa domiategatie fom of dyami aGTPase eqied fo edocytic membaefsio ihibited this ptake. This implies

that the edocytic machiey is ioledi this pocess35(FIG. 2b). Amyloid fibils,icldig those associated with systemicamyloid disease48 ad those ot omallyfod i ekayotes49, ca be itealizedby clted cells, possibly by beachig theplasma membae (FIG. 2b). Althogh these

fidigs aise the possibility that mammalia cells might hae a geate abilityto itealize odeed fibilla aggegatestha peiosly thoght, fthe stdiesae eqied to destad the moleclamechaisms.

Ee if eos ad othe mammaliacells take p fibilla aggegates by edocytosis, i ode fo them to cleateaggegatio of edogeos cytoplasmicpoteis, which is essetial fo the piolikehypothesis, they mst escape the itacellla

esicle ad gai access to the cytoplasm. Theaggegates iestigated i the cell cltestdies descibed aboe ae too pola to diffse passiely acoss lipid bilayes ad toolage to pass thogh tasmembae poeso taspotes. noetheless, extacelllaaggegates cotaiig polygltamie42, ta39ad syclei34 hae ow bee show toete cells ad case seedig of edogeos

poteis. Deepetch electo micoscopeimages of polygltamie aggegates shotlyafte itealizatio ito clted cellseealed aked aggegates o the cytoplasmic face of the plasma membae. Theewas o eidece of a sodig membaos stcte42, sggestig that aggegatesca peetate the plasma membae i theabsece of esicla ptake. Stdies i atificial systems o syclei oligomes showthat they ca ede lipid bilaye membaespemeable to floescet dyes, sggestigthat syclei aggegates ca itecalatediectly ito lipid membaes50. This po

ides a potetial meas by which aggegatescold exit fom edosomes o pehaps cossthe plasma membae diectly. Fially,it is possible that tellig aotbes 50200 m diamete actiich hollowfilamets see betwee itecoected cellsi clte51 ca act as taspot coditsfo piolike potei aggegates, as has beesggested fo PP51(FIG. 2c).

Ccluss ad perspectves

Seeal eodegeeatie diseases haesymptomatic oset i mid o late life ad

ofte hae potacted coses. This iseidet i domiatly iheited familialdiseases sch as Htigtos disease adae familial foms of Alzheimes diseasead Pakisos disease, i which the cetaleos system copes with the cotiedsythesis of mtat, aggegatiopoepoteis fo may decades befoe eetally exhibitig eopathology. Cellladefeces, sch as those descibed i BOX 2,pobably sppess the fomatio of aggegatio clei dig this latet peiod. Ithese diseases, as with the moe commo

Fgur 3 | Pp p p . | intrallular protn aggr-

gat an b rlad from nuron by xoyto or ll dath. Th aggrgat ar takn up by, for

xampl, adjant nuronal ll bod and ar thr rtand n th ll oma (loal prad of path-

ology) or tranportd antrogradly by axon. Altrnatly, thy ar takn up by axon trmnal and

tranportd rtrogradly to th ll oma. Th protn aggrgat an prad btwn bran rgon

by axonal tranport. b | Thr drawng propo prnpl for how nuropathologal hang n

Parknon, Alzhmr and Huntngton da prad patotmporally durng da progr-

on. Th arlr th nuropathology dlop n a gn bran rgon, th darkr th hadng n th

dagram. A only on w (md-agttal for Parknon and Alzhmr da; latral for Huntngton

da) of th bran dptd for ah dordr, not all rlant anatomal trutur and dtal of

th pradng pattrn (ndatd by arrow) ar prntd. b | in Parknon da, -ynulnaggrgat (Lwy nurt and Lwy bod) ar uggtd to frt appar n th doral motor nulu

of th agal nr n th brantm and antror olfatory trutur (darkt grn), and thn to prad

trotypally to fnally oupy larg part of th bran4,5. | in Alzhmr da, nurofbrllary tan-

gl frt appar n th hppoampu (and loly aoatd trutur), th baal nulu of Mynrt

and th brantm1518(darkt grn). Thy prad to othr bran rgon, nludng th noortx, n a

trotypal mannr, orrlatng wth ymptomat progron. | in Huntngton da, th puta-

mn and audat nulu, and rlatd baal gangla trutur dp nd th bran (darkt grn),

ha bn uggtd to dgnrat frt2527. Howr, rnt magng tud uggt that prmary

motor and nory ort alrady undrgo atrophy n pr-ymptomat gn arrr28. Thrfor

w propo that ortal nolmnt prd baal gangla pathology.





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idiopathic diseases, the low pobabilityof spotaeos misfoldig ad aggegatio of coectly folded cellla poteisito pathogeic aggegates might explaiwhy disease oset is typically i mid life olate. Followig the lag phase, itecelllatasfe of poteis might ee hae a olei the popagatio of eopathology i thegeetic eodegeeatie disodes. Ths,oce aggegated poteis hae appeaed ia stochastic mae they may be extdedfom a iitiatig sbpoplatio of cells adspead to eighboig eos.

Whethe piolike tasmissio mechaisms actiely cotibte to the pathogeesisof idiopathic eodegeeatie diseasesemais clea. We caot exclde thatdiseaseelated poteis tasfe betweeidiidals thogh the se of cotamiatedsgical tools o o tisse tasplat, bt theeae o epots to sppot this. If piolike

tasmissio has a ole, it seems moe likelyto cotibte to the gadal speadig ofeopathological chages i the bais ofafflicted idiidals. Impotatly, the possibleexistece of extacellla itemediates ithe pogessio of what peiosly hae beecosideed stictly cellatoomos itacellla disodes, poides a hitheto appeciated extacellla stage i pathogeesis.This extacellla step i the pathogeesismay epeset a moe eadily accessible tagetfo oel theapetic iteetio.

Patrik Brundin is at the Neuronal Survival Unit,

Wallenberg Neuroscience Center, Lund University,

BMC A10, 221 84 Lund, Sweden.

Ronald Melki is at the Laboratoire dEnzymologie et

Biochimie Structurales, Centre National de la Recherche

Scientifique, 91198 GifsurYvette, France.

Ron Kopito is at the Department of Biology, Stanford

University, Stanford, California 943055020, USA.

emails:[email protected];

[email protected];[email protected]

doi:10.1038/nrm2873

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AcknowledgementsAll three investigators are supported by a joint Human Frontier

Science Program grant on the topic relevant to this article. In

addition, P.B. holds related grants from the MJ Fox Foundation

for Parkinsons Research, Swedish Brain Foundation, Swedish

Parkinson Foundation, Sderberg Foundation and the Swedish

Research Council. R.R.K. is supported by the Huntingtons dis-ease Society of America Coalition for the Cure, the CHDI

Foundation and the National Institute of Neurological Disease

and Stroke. R.M. is supported by the Agence Nationale de la

Recherche and the Centre National de la Recherche

Scientifique. R.M. and P.B. are part of the ERA-net Neuron

program MIPROTRAN.

Competing interests statementThe authors declare no competing financial interests.

DATABASESOMiM:http://www.nb.nlm.nh.go/omm

Alzhmr|Huntngton| Parknon

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Artigo 17 - Prion-Like Transmission of Protein Aggregates in Neurodegenerative Diseases

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