PROTEIN AGGREGATION AND ASSOCIATED NEURO-DEGENERATIVE

DISEASES
Sumanta Kar
Department of Biotechnology and Medical Engineering, NIT Rourkela
Rourkela , Odisha; India
Abstract Neurodegenerative diseases are specified by selective
neuronal susceptibility and neurodegeneration in specific brain
regions. The pathogenesis of these disorders mainly involves
abnormal accumulation and aggregation of specific proteins
(such as polyglutamine, -synuclein, amyloid and tau), which
are deposited in intracellular inclusions or etracellular
aggregates that are characteristic for each disease. !rotein
aggregation is due to specific interactions between partially
folded intermediates. "nce formed, aggregates tend to be
resistant to degradation. #ells have adapted a mechanism to
avoid the accumulation of incorrectly folded proteins. $n
neurodegenerative disorders, this cellular disposal mechanism
becomes ineffective and as a result, misfolded proteins
accumulate and become toic for distinctive sets of neurons. This
results in clinical manifestation of disease.
Keywords aggregation , neurodegeneration ,misfolding ,
amyloid , tau , polyglutamine , -synuclein
I. INTRODUCTION
Proteins are essential comle! macromolecules o" or#anisms
an$ articiate in actuall% e&er% rocess 'it(in cells. T(ree
$imensional structures o" roteins la% an in$isensa)le role
"or )iolo#ical "unctions. T(ere"ore* t(e% must un$er#o roer
"ol$in# in or$er to er"orm t(ese "unctions. +o'e&er* ne'l%
s%nt(esi,e$ roteins ma% not "ol$ correctl%. Conse-uentl%*
t(e% 'ill (a&e a stron# ten$enc% to a##re#ate. +eat s(oc.
roteins /c(aerones0 la% an instrumental role in correctin#
rotein "ol$in# an$ re&ention o" rotein a##re#ation. Protein
a##re#ates (as to!ic e""ects '(en accumulate$ o&er a certain
amount in t(e cell. T(e accumulation o" a)normal roteins
lea$s to ro#ressi&e loss o" structure an$1or "unction o"
neurons* inclu$in# t(e $eat( o" neurons. 2an% $iseases
associate$ 'it( rotein a##re#ation suc( as rion* Al,(eimer3s
/AD0* Par.inson3s /PD0* an$ +untin#ton3s $iseases /+D0.
2an% o" t(e neuro$e#enerati&e $isor$ers are li.el% to occur
$ue to en&ironmental an$ #enetic "actors. In a$$ition*
li.eli(oo$ o" )ein# a""ecte$ 'it( 1occurrin# AD an$ PD rises
'it( increasin# a#e. At t(e cellular le&el*man%
neuro$e#enerati&e $isor$ers s(o' similarit% in t(e
$e&eloment o" at(o#enesis an$ neuronal $eat(. Alt(ou#(
t(ere is a consi$era)le $e)ate re#ar$in# t(e to!icit% &ersus
rotecti&e e""ect o" a##re#ates* rotein mis"ol$in# aears to
)e a common "eature o" ro#ressi&e neuronal $%s"unction an$
$e#eneration. 2oreo&er* mec(anisms o" rotein a##re#ations
an$ #eneration o" neuro$e#enerati&e $iseases 'it( mis"ol$e$
roteins (a&e not )een eluci$ate$ roerl% %et. T(ere"ore* t(e
aim o" t(is re&ie' is to )rin# a ersecti&e to t(e role o"
mis"ol$e$ roteins in neuro$e#enerati&e $iseases in terms o"
molecular )asis.
II. AN OVERVIE4 ON PROTEIN AGGREGATION
$ Protein a##re#ation is a (enomenon '(ere rotein clum
to#et(er an$ accumulate to "orm clums or a##re#ates* '(ic(
are mostl% to!ic5 in #eneral t(e mis"ol$e$ roteins are t(e
one3s associate$ 'it( t(e to!icit%. Protein a##re#ation can )e
o" t'o t%es6 naturall% occurrin#* ro$ucti&e a##re#ation*
'(ere in a##re#ation o" correctl% "ol$e$ monomers a##re#ate
to "orm ol%mers o" t(e same roteins. /E#. 2onomeric G-
actin* a##re#ates to "orm 7ilamentous 7-actin 8 in&ol&e$ in
maintainin# t(e s(ae o" cells0 an$ un'ante$ a##re#ation*
'(ere in mis"ol$e$ roteins a##re#ate an$ are to!ic to t(e
s%stem. /roteins suc( as 9-s%nuclein* :-am%loi$*
ol%#lutamine '(ic( a##re#ate an$ are in&ol&e$ in neuro-
$e#enerati&e $iseases0
Proteins #reater t(an ;<< amino-aci$s un$er#o assiste$
rotein "ol$in# 'it( t(e (el o" c(aerones an$ c(aeronins.
T(ere is se-uential "ol$in# o" elementar% "ol$in# units calle$
"ol$ons* t(us t(e rotein "ol$s to its correct nati&e
con"ormational =D s(ae in t(e cell. +o'e&er t(ere are man%
e&ents t(at coul$ cause t(e mis"ol$in# o" t(e rotein an$
$iscreancies in t(e "ol$in# mec(anism suc( as62utations in
t(e co$in# se-uence o" rotein *2isrocessin# o" t(e rotein
ol%eti$e*C(an#es in t(e "ol$in# en&ironment* O!i$ati&e
stress on rotein* Association o" ions 'it( roteins (in$erin#
t(eir "ol$in#. 2ostl% t(e mis"ol$e$ roteins associate$ 'it(
neuro $e#enerati&e $isease are relate$ 'it( re$uce$
e!ression o" c(aerone or re$un$anc% in c(aerone acti&it%
'(ic( ai$s in t(e rotein mis"ol$in# mec(anism.
T(e rotein a##re#ates can )e classi"ie$ into > t%es6
amor(ous a##re#ates 8 '(ic( are #ranular* an$ (a&e
$isor$ere$ ol%eti$e c(ains* 'it( enric(e$ :-s(eets '(ic(
#lue t(e macromolecular structure. /E#. ?-cr%stallin "oun$ in
cataract $isease$ con$ition0 an$ am%loi$ "i)rils 8 '(ic( are
(i#(l% or$ere$ an$ reetiti&e '(ere all ol%eti$es a$ot a
common-"ol$ /i.e. t(e :-s(eets are oriente$ eren$icular to
t(e "i)ril a!is.0
To outline t(e rocess o" rotein mis"ol$in# * a mis"ol$e$
rotein monomer is t(e startin# comonent '(ic( )ecomes
acti&e i.e. $ue to its e!ose$ (%$ro(o)ic resi$ues attracts
similar mis"ol$e$ monomers to a##re#ate. T(is ste is t(e
nucleation ste. T(e a##re#ation continues until it "orms eit(er
an amor(ous or am%loi$ a##re#ate. Usuall% in t(e s%stem
'(en t(ere is a case o" rotein mis"ol$in#* t(e s%stem tries to
re"ol$ it )ac. to its nati&e con"ormation )% t(e (el o"
c(aerone molecules suc( as +s-@<* +s-;<< /un"ol$ers 8
'(ic( (el un"ol$ t(e mis"ol$e$ rotein0* +s@< an$ +s-;<
/c(aerones '(ic( (el in correct "ol$in# o" t(e un"ol$e$
rotein0* (ence t(e ener#% re-uirement )% t(e mis"ol$e$
rotein is (i#( comare$ to t(e normal rotein '(ic( "ol$
roerl%. +o'e&er in case o" mis"ol$e$ roteins associate$
'it( neuro-$e#enerati&e $iseases t(e% are mutate$ an$ t(e
c(aerone s%stem is also $o'n-re#ulate$ an$ so t(e s%stem
cannot com)at t(e rotein a##re#ation o" suc( mis"ol$e$
roteins* '(ic( e&entuall% "orms amor(ous or am%loi$
a##re#ates $ue to intermolecular interactions. T(e a##re#ates
"orme$ are resistant to u)iti-uitin me$iate$ roteasome
$estruction* an$ also (a&e no a""init% "or c(aerone an$
lea$in# to accumulation o" t(e a##re#ates '(ic( is to!ic.T(e
amor(ous a##re#ates (a&e muc( smaller si#ni"icance in t(e
neuro-$e#enerati&e con$itions* '(ere in it is t(e am%loi$ "i)ril
"ormation '(ic( a&es 'a% "or t(e $isease$ con$ition.T(e
rocess o" am%loi$ "i)ril "ormation "ollo'in# Anucleation an$
elon#ationB mo$el* can )e $i&i$e$ into t(ree (ases 6
T(e t(ermo$%namicall% $is"a&oure$ la# (ase '(ere
t(e solu)le secies /usuall% monomers0 associate to
"orm nuclei. T(e s%stem tries to a&ert t(e am%loi$
"ormation )% &arious mec(anism me$iate$ )%
c(aerones or roteasome me$iate$ an$ (ence t(is
(ase is (i#(l% $is"a&oure$ in t(e s%stem. It is a
oorl% c(aracteri,e$ state '(ic( "ormation
in"luences t(e o&erall .inetics o" t(e am%loi$
reaction.
T(e e!onential (ase '(ere t(e nuclei "ormation
lea$s to accumulation o" more monomers '(ic(
a##re#ate in an or$ere$ manner to "orm roto-"i)rils.
T(e oulation o" t(ese transient assem)lies tri##ers
t(e ol%meri,ation.
7inall%* t(e e!(austion o" monomers lea$s to t(e
saturation (ase '(ere no more solu)le secies can
associate to t(e en$s o" re"orme$ "i)rils an$ "i)ril
maturation occurs* usuall% )% lateral association o"
roto-"i)rils.
III. +UNTINGTON3S DISEASE
+untin#ton $isease /+D0 is an autosomal $ominant ol%-
#lutamine $isor$er. T(e a""ecte$ in$i&i$uals e!(i)it
in&oluntar% Cer.% mo&ements an$ alterations in memor% an$
moo$ an$ t(ere is a selecti&e loss o" striatal neurons. T(e #ene
Dhuntington3 resent in t(e s(orter arm o" t(e E
t(
c(romosome*
#i&es rise to t(e rotein D+untin#tin3 '(ic( is =F<.Da in
'ei#(t (a&in# =;EE amino aci$s. T(e +untin#ton rotein is
mostl% re&alent in t(e neurons in t(e neo-corte!* cere)ellar
corte!* striatum an$ (iocamus. +untin#tin rotein la%s a
crucial role in t(e ner&e cell "unction suc( as intracellular
transort* re#ulation o" transcrition* in(i)ition o"
ro#ramme$ cell $eat( an$ also resonsi)le "or $e&eloment
o" central ner&ous s%stem in t(e earl% em)r%o. T(e
+untin#ton $isease is cause$ '(en t(ere is a mutation in t(is
D(untin#ton3sB #ene lea$in# to a mutant rotein '(ic( cannot
"ol$ roerl%. T(e F3 en$ o" t(e #ene (as CAG reeats5 CAG
/C%tosine-A$enine-Guanine0 trilet co$on is resonsi)le "or
t(e co$in# t(e amino aci$ 8 #lutamine-/G0. T(e CAG co$on
#ets e!an$e$ lea$in# to e!cess num)er o" #lutamine in t(e
$e"ecti&e rotein. Normal (untin#tin rotein (as ;<-=F
#lutamine reeats* '(ereas mutant rotein (as more t(an E<
reeats. T(is ol%G tract near t(e N-terminus o" t(e rotein is
resonsi)le "or t(e mis"ol$in# o" t(e rotein an$ "ormation o"
SDS-insolu)le am%loi$ "i)rils. T(e ol%G se-uences con&ert
"rom a lar#el% $isor$ere$ structure into a )-s(eet-ric(
con"ormation uon a##re#ation. T(ese "i)rillar structures
resem)le t(ose "orme$ )% roteins imlicate$ in ot(er
am%loi$-relate$ neuro$e#enerati&e $iseases H;I. T(e amino
aci$* #lutamine is olar in nature5 an$ t(e o&era)un$ance o"
#lutamine causes lin.s to "orm 'it(in an$ )et'een roteins.
T(e rotein /mis"ol$e$0 molecules Astic.B to one anot(er*
"ormin# stran$s t(at are (el$ to#et(er )% (%$ro#en )on$s*
rat(er t(an "ol$in# into "unctional roteins* t(e% $e&elo into
tan#le$* ri#i$ #rouin#s .no'n as rotein a##re#ates. T(e
rotein a##re#ates 'it( e!ose$ (%$ro(o)ic atc(es #ets
ali#ne$ in an or$ere$ manner to "orm am%loi$ "i)rils* 'it(
t(eir :-s(eets eren$icular to t(e "i)ril a!is.In a rocess
similar to t(e "ormation o" a##re#ates* t(e e!cess #lutamines
in t(e mis"ol$e$ rotein can also lea$ to a t%e o" rotein
)un$lin# .no'n as neuronal inclusions /NI0* or inclusion
)o$ies. NIs initiall% "orms at t(e a!ons an$ $en$rites o" ner&e
cells in seci"ic areas o" t(e (uman )rain* ro$ucin# t(e
$ama#e$ neurons c(aracteristic o" +D.Su)se-uentl%* $ue to
misrocessin# o" t(e mutate$ ol%eti$e or $ue to t(e
alternate slicin# o" t(e mutate$ mRNA* smaller "ra#ments o"
t(e $e"ecti&e rotein are ro$uce$. T(ese smaller mis"ol$e$
$e"ecti&e ol%eti$es enter t(e ner&e cell nuclei* "ormin#
more clums at t(e centrosomes "ormin# inclusions an$
lea$in# to neuro-$e#enerati&e con$itions.
IV. AJK+EI2ER3S DISEASE
Al,(eimer3s $isease /AD0 is t(e most "re-uent t%e o"
neuro$e#enerati&e $isor$er* common cause o" co#niti&e
imairment in el$erl% eole aroun$ t(e 'orl$. In ;L<@* AD
'as "irst $escri)e$ )% s%c(iatrist an$ at(olo#ist Dr. Alois
Al,(eimer an$ t(en t(e $isease 'as name$ 'it( (is surname.
T(e AD a""ecte$ in$i&i$uals su""er "rom a massi&e loss o"
neurons. Alt(ou#( AD atients $e&elo memor% imairment*
t(e% sur&i&e M8;< %ears a"ter t(e onset o" s%mtoms. T(e
(isto-at(olo#ical si#ns o" AD in&ol&e t(e resence o"
coious amount o" neuritic la-ues an$ neuro"i)rillar%
tan#les /N7Ts0. T(e senile la-ues mostl% consist o" :-
am%loi$ /A:0 eti$e an$ t(e N7Ts are intracellular
a##re#ates o" (%er(os(or%late$ microtu)ular tau roteins.
It (as )een t(ou#(t t(at t(e "ormation o" la-ues "acilitates t(e
initiation t(e "ormation o" N7T. AD is a #eneticall% comle!
$isor$er o" t(e el$erl% an$ "amil% (istor% is associate$ 'it(
increasin# ris. o" $e&eloin# AD. It is most li.el% associate$
'it( #enes an$ en&ironmental "actors. In "amilial AD* a
#enetic contri)ution is clearl% e&i$ent. To $ate* t(ree #enes6 :-
am%loi$ recursor rotein /APP0 #ene /locate$ on
c(romosome >;0* resenilin ; /PS;0 /on c(romosome ;E0 an$
resenilin > /PS>0 /c(romosome ;0 '(en mutate$ cause earl%-
onset "amilial AD. In a$$ition* ol%mor(isms in "our #enes6
aoliorotein E /ao E0* 9-> micro#lo)ulin* &er% lo' $ensit%
liorotein recetor an$ lo' $ensit% liorotein recetor-
relate$ rotein /JRP0 are s(o'n to )e ris. "actors "or AD
at(o#enesis. In t(is resect* it is interestin# t(at ao E*
am%loi$ : rotein an$ 9-> micro#lo)ulin are li#an$s to JRP
an$ t(e% are resent in senile la-ues.T(e resence o" t(e NE
allele o" ao E is associate$ 'it( an increase$ ris. o" AD in
'(ite an$ Asian oulation as oose$ to Olac. an$ +isanic*
)ut t(e at(o#enic mec(anism is un.no'n. All t(ree mutant
#enes /APP* resenilins ; an$ >0 increase t(e ro$uction o" :-
am%loi$ eti$e '(ic( is $eosite$ in neuritic la-ues. T(e :-
am%loi$ #ene enco$es a transmem)rane am%loi$ recursor
rotein. T(e insolu)le A: eti$e ro$uction re-uires
roteol%tic clea&a#e o" APP. T(is in&ol&es t'o stes6 t(e "irst
clea&a#e is ac(ie&e$ )% :-secretase at met(ionine @M; o" APP
an$ t(e secon$ clea&a#e is at t(e C-terminal o" A )% P-
secretase H>I. T(e microtu)ule associate$ rotein tau is t(e
maCor constituent o" N7T an$ is mainl% "oun$ in a!ons.
+%er(os(or%late$ tau ma% $esta)ili,e t(e microtu)ule
net'or. )ecause o" its ina)ilit% to )in$ microtu)ules an$
romote t(eir assem)l%. It ma% also imair a!on transort an$
contri)ute to N7T "ormation an$ ultimatel% neuronal $eat(
H>I.

V. PARKINSON3S DISEASE
Par.inson3s $isease is a late-onset neuro$e#enerati&e $isor$er*
'(ic( is c(aracteri,e$ )% muscular ri#i$it%* ostural
insta)ilit% an$ restin# tremor. It is a slo'l% ro#ressi&e
$isor$er an$ t(e at(olo#% o" PD in&ol&es t(e $e#eneration o"
$oaminer#ic neurons in t(e su)stantia ni#ra. T(e clinical
(allmar. o" PD is t(e $eosition o" intra-c%tolasmic
inclusion )o$ies calle$ Je'% )o$ies in )rain cells. T(e
mec(anism )% '(ic( $oaminer#ic neurons are selecti&el%
lost is not un$erstoo$. T(e role o" #enetics in PD (as al'a%s
)een contro&ersial. +o'e&er* "amilial a##re#ation stu$ies
su##est t(at late-onset PD (as a si#ni"icant #enetic etiolo#%.
+erita)le "orms o" PD are cause$ )% mutations in #enes. To
$ate* t(ree #enes /9-s%nuclein* ar.in an$ u)i-uitin C-
terminal (%$rolase J; /UC+J;00 are s(o'n to )e associate$
'it( "amilial "orms o" PD H=*EI .Autosomal $ominant PD
results in mutations in t(e 9-s%nuclein #ene an$ autosomal
recessi&e PD is $ue to mutations in t(e ar.in #ene. In t(e
case o" t(e ar.in #ene* it is not onl% t(e recessi&e loss o"
ar.in t(at is a ris. "actor "or Cu&enile an$ earl%-onset
Par.insonism* )ut (etero,%#ous mutation coul$ also )e a ris.
"actor. Amon# ot(er "actors* aoliorotein E N>1NE #enot%e
mi#(t )e a ris. "actor "or sora$ic PD. +o'e&er* Se&eral lines
o" e&i$ence su##est t(at in all .no'n "orms o" PD* rotein
a##re#ation in $oaminer#ic neurons o" t(e su)stantia ni#ra is
t(e common mec(anism o" neuro$e#eneration. 7or instance*
all t(ree roteins mentione$ a)o&e are resent in Je'% )o$ies
in sora$ic PD an$ in $ementia 'it( Je'% )o$ies.
Accumulation o" 9-s%nuclein in culture$ (uman cells also
selecti&el% $e#enerates $oaminer#ic neurons in resence o"
$oamine )ut not non-$oaminer#ic neurons su##estin# a
selecti&e to!icit% o" its accumulation. It is ossi)le t(at 9-
s%nuclein ma% rotect an$ (el neurotransmitter &esicles to
transort t(em "rom cell )o$% to s%nase. Its a##re#ate ma%
e!ert its to!icit% )% creatin# ores in t(e lii$ mem)rane. T(is
ma% lea$ to loss o" $oamine "rom &esicle to c%tolasm.

VI. PRION DISEASE
Prion $isease is t(e )est e!amle to s(o' t(at rotein
con"ormational c(an#e can e&en lea$ toin"ectious $isease.In
t(e %ear o" ;LQ>* rion term coine$ )% Stanle% Prusiner an$
co-'or.ers "rom !proteinaceous infectious particle" Prion
rotein is "oun$ in t'o $i""erent "orms6 a cellular "orm o"
rion rotein /PrPc0 an$ scraie iso"orm o" rion rotein
/PrPSc0 HFI. Proerl% "ol$e$ "orm is $enote$ as PrPc '(ile
mis"ol$e$ "orm is $enote$ as PrPSc . T(e PrPc is an 9-(eli!-
ric( #l%corotein t(at is aro!imatel% >F< amino aci$s in
len#t(. It is enco$e$ )% t(e prion protein gene #$rpn% '(ic( is
locate$ on c(romosome >< HMI. PrPc is commonl% "oun$ on
neuronal cell mem)rane )% a #l%cos%l (os(ati$%linositol
/GPI0. +o'e&er* it is also e!resse$ on ot(er cells suc( as
leu.oc%tes an$ $en$ritic cells. PrPc is (i#(l% conser&e$
rotein amon# mammals $urin# e&olution. 4(en 'e e!amine
t(e rimar% structure o" t(e rotein* PrPc consist o" a si#nal
eti$e * "i&e octaeti$e reeats * a (i#(l% conser&e$
(%$ro(o)ic $omain* an$ a GPI /#l%cols%l (os(ati$%l-
inositol0 anc(or. 7urt(ermore* PrPc contains t'o N-lin.e$
#l%cos%lation sites. PrPSc can )e $e"ine$ as an in"ectious
iso"orm o" PrPc an$ causes "atal rion $iseases. PrPSc is
"orme$ )% mis"ol$in# o" PrPc 'it( a lost in 9-(elical content.
PrPSc (as same amino aci$ se-uence 'it( PrPc* )ut t(eir
secon$ar%* tertiar%* an$ -uarternar% structures are $i""erent HMI.
Aro!imatel%* PrPc inclu$es =R :-structure an$ EMR 9-(eli!
structure* )ut nonet(eless PrPSc is comose$ o" E=R :-
structure an$ =<R 9-(eli! structure. It )ecomes non-solu)le
an$ resists to roteol%tic $e#ra$ation 'it( con"ormational
c(an#es* '(ereas PrPc is solu)le an$ rotease sensiti&e. T(is
insolu)le rotein accumulates in )rain an$ causes a &ariet% o"
rion $iseases in (uman an$ animals HMI. 7urt(ermore*
interaction o" PrPc 'it( mem)rane lii$ la%ers la% a
si#ni"icant role in con&ersion o" PrPc to PrPSc. PrPc is
locali,e$ in c(olesterol an$ s(in#om%elin ric( area on cell
sur"ace /.no'n as lii$ ra"t0 H@I. PrPc is )oun$ to lii$
mem)ranes t(rou#( its GPI anc(or. 4(ile lea&in# PrPc "rom
t(e mem)ranes )% catal%sis o" (os(ati$%linositol
(os(oliase C /PIPJC0* PrPSc s(o' resistance to PIPJC.
4(en )in$in# o" PrPc to t(e lii$ mem)ranes* PrPc is
$e#ra$e$ or con&erte$ into PrPSc "orm HMI. T(e #rou o" rion
$iseases* inclu$in# Creut,"el$t-Sa.o) /CSD0* "atal "amilial
insomnia /77I0* Kuru* Gerstmann-StrTussler-Sc(ein.er
s%n$rome /GSS0 are seen in (umans* an$ in similar "as(ion
scraie* )o&ine son#i"orm ence(aloat(% /ma$ co'
$isease0* c(ronic 'astin# $iseases /C4D0* transmissi)le min.
ence(aloat(% /T2E0* "eline son#i"orm ence(aloat(%
/7SE0 $iseases are o)ser&e$ in animals HMI. All o" t(ese
$iseases #i&e similar neurolo#ical s%mtoms suc( as
$%smnesia* $eression* sense $istur)ances* an$ s%c(osis HMI.
VII. CONCJUSIONS
Al,(eimerUs $isease* +untin#tonUs $isease* rion $iseases an$
Par.insonUs $isease are c(aracteri,e$ )% ro#ressi&e ner&ous
s%stem $%s"unction. T(e% in&ol&e $eosition o" mis"ol$e$
roteins suc( as :-am%loi$ * (untin#tin * rion an$ 9-
s%nuclein resecti&el%. Protein a##re#ation is $ue to seci"ic
interactions )et'een artiall% "ol$e$ interme$iates. Once
"orme$* a##re#ates ten$ to )e resistant to $e#ra$ation. Cells
(a&e a$ate$ a mec(anism to a&oi$ t(e accumulation o"
incorrectl% "ol$e$ roteins. In neuro$e#enerati&e $isor$ers*
t(is cellular $isosal mec(anism )ecomes ine""ecti&e an$ as a
result* mis"ol$e$ roteins accumulate an$ )ecome to!ic "or
$istincti&e sets o" neurons. T(is results in clinical
mani"estation o" $isease. Alt(ou#( man% o" t(ese $isor$ers
"orm rotein a##re#ates 'e are still i#norant a)out t(eir
comosition* causes o" mis"ol$in# an$ (o' accumulation o"
mis"ol$e$ rotein )ecomes to!ic "or t(e cell . T(ere is stron#
e&i$ence o&er t(e ast $eca$e t(at su##ests t(at a$ult (uman
)rain (as an en$o#enous oulation o" stem cells. T(ese cells
are multiotent an$ at least in t(e ro$ent )rain t(e% can )e
in$uce$ to roli"erate )% &arious #ro't( "actors. +o'e&er*
t(ese cells $o not aear to relace t(e lost cells in
neuro$e#enerati&e $isor$ers. T(is coul$ )e $ue to se&eral
"actors suc( as "ailure to ro$uce aroriate si#nals or
ro$uction o" in(i)itor% si#nals )% $e#eneratin# neurons.
Alternati&el%* it is also ossi)le t(at t(e rate o" cell loss is
#reater in t(e $isease state t(an t(e rate o" stem cell $i&ision.

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