neirodegeneraciuli

d v de e
daavadebebi

daunis
d u sindromi
d
II
 farmakoTerapiuli samizmeebis gamoyeneba
molekuluri meqanizmebis darRvevisas

Ts65Dn
T 65D virTagvebSi
r bS CCatarebulia
r b kvlevebi,
b r romelic
m
mimarTulia mexsierebis gaumjobisebisken Semdegi gzebis
darRvevebis Tavidan acilebis gziT

• serotoninis sasignalo gza

• NMDA receptoris sasignalo gza
• neirodacviTi
e d cv gza
g
• oqsidaciuri stresis gza
 serotoninis sasignalo gza

serotoninis roli neiroplastiurobaSi

serotoninis
r n n gamomamuSavebeli
m m m b neironebi
n r n b viTardeba
r b
ZuZumwovrebis tvinSi ganviTarebis adreul stadiaSive.
g asrulebs
igi ule did
d d rols
l tvinis
tv mravali
v l regionis
eg
ganviTarebisa da momwofebis procesSi.
am neironebis farTod gavrceleba da adreul stadiaze
misi g
ganviTareba
v e miuTiTebs
u e serotoninis
e t did
d d rolze
l e
sinafsuri plastiurobis ganxorcielebisa da misi
stimulirebis procesSi
ds is mqone individebSi SeimCneva:
ds-is SeimCneva
• hipokampis ujredebis raodenobis Semcireba
mizezi:
• neirogenezSi mimdinare SeferxebebiT SeiZleba iyos
ganpirobebuli
np r b b
(es mtkicdeba Ts65Dn da Ts1Cje virTagvebSi)
Sedegi:
• es iwvevs mexsierebisa da daswavlis darRvevebs
(hipokampaluri neirogenezis zrda iwvevs Semecnebis unaris gaumjobesevas)

am procesebSi CarTulia serotoninis sasignalo gza,

kerZodes darRvevebi miiRweva HSA21- qromosomaze
arsebuli KCNJ6 genis trisomiis xarjze
 serotoninis (5-Hhidroqsitri ptamini (5-HT)) receptoris (5HTR 1A)
gaaqtivebis
q x r z G cila daWiSkruli
b s xarjze, W S r K arxebis
K+ rx b s SuamavlobiT
S m b
xdeba hi pokampSi zrdasruli individebis neirogenezi
G ccila
l d W k ul K+ arxebi
daWiSkruli e e c ve KCNJ6 ge
Seicaven genis produqts-
duqt
GIRK2 suberTeulis saxiT

5HTR 1A - G cila Sewyvilebuli

receptori, axorcielebs
mainhibirebel neirotransmisias
 KCNJ6 genis
n s zeeqspresia
z qspr s (trisomiisas)
( r s m s s) iwvevs:
w s

• kaliumis ionebis ujredidan gandinebis gaZlierebas,

• xdeba neironis hi perpolarizacia
• mcirdeba ujredis agznebadobas
• mcirdeba serotoninis gamoTavisufleba
 problemis daZleva:
gavzardoT
g v d serotoninis
e t gamoTavisuflebis
g v ufle done
d e

fluqsetini (SerCeviTad serotoninis ukuSTanTqmis inhibitori)

• ainhibirebs GIRK receptors

• blokirdeba serotoninis ukuSTanTqmis
transporterebi
• aRar
R xdeba
de serotoninis
e t uku
ukuSTanTqma
q
presinafsSi
• izrdeba serotoninis done
• Zlierdeba serotoninis receptorebis
moqmedeba
(masze serotoninis xanZlivad moqmedebis xarjze)
• zrdis
zr s hih pokampul
p ampu n neirogenezss
r n zss
• aRdgeba mexsierebisa da daswavlis
procesi

http://www.youtube.com/watch?v=ocSptPUBbuo&feature=related
 serotoninis efeqti unda regulirdebides S100B
cilis saSualebiTac

maT Soris vl
vlindeba
de urTierTreci
u e ec prokuli
kul kavSiri
k v
kerZod:
serotonini (5-HT1A
receptorebis saSualebiT)
ganapirobebs ujredidan
S100B–is gamoaTavisuflebas,
g v ufle

Tavis mxriv:

S100B ganapirobebs
serotoninis terminalebis
ganviTarebas

rig SemTxvevebSi cilis S100B zeeqspresiis paralelurad adgili

aqvs serotoninis raodenobis Semcirebas ujrebSi
 21 qromosomis sruli trisomiisas procesSi
erTveba S100B cila
S100B-cila

• Ca2+ damakavSirebeli cila

• eqspresirdeba ZiriTadad cns-is astrogliur ujredebSi,
mcire raodenobiT gvxvdeba aseve neironebSi,
mikrogliasa da oligodendrocitebSi
• aregulirebs ujredul cikls
• monawileobs tvinis ganviTarebisa da mis aRdgeniT
procesebSi
• regulirdeba oqsidaciuri mdgomareobiT
• iwvevs neironebis gadarCenas oqsidaciuri stadiisas
• iwvevs apoptozs da neirotoqsiuribas SedarebiT mcire
stresis pirobebSi
• misi raodenobis cvlileba gavlenas axdens mexsierebisa
da daswavlis procesze transgenul virTagvebSi
 S100 beta-s moqmedeba koncentraciazea
damokidebuli

dabali koncentraciiT maRalia koncentraciiT

proteqtuli toqsiuri
qs r
da da
trofikuli
t f kul proapoptozuri
Tviseba Tvisebis

S100 beta-s momatebuli raodenoba SeimCneva dauniT daavadebulTa

Tavis tvinsa da sisxlSi, misi zeeqspresia Canasaxovani tvinis
ganviTarebis
g v e procesSi
ce unda
u d iyos
y mizezi
e g
gonebrivi
e v
Camorcenilobis procesSi
NMDA receptoris sasignalo gza
NMDA receptoris
ece t an/da
d kalcineurinis
k lc eu
aqtivoba damokidebulia HSA21- qromosomis 9
genze: • APP
• TIAM1
• BACH1
• SOD1
• SYNJ1
• ITSN1
• RCAN1
• DYRK1A
• PCP4

(NMDA receptori –ionotropuli glutamatis receptori)

CarTulia sinafsur plastikurobasa da mexsierebis
procesebSi).
procesebSi)
misi arakonkurentuli antagonistia: MK-801, memantini
 kalcineurini
kalcineurini warmoadgens kalciumdamokidebul
proteinfosfatazas

Tavis tvinSi misi moqmedeba dakavSirebulia:

• NMDA receptorebTan,
• GABA-ergul receptorebTan
• dofaminergul receptorebTan

misi nakleboba tvinSi iwvevs:

• darRvevebs sinafsur plastikurobaSi

• m xs r b s daqveiTebas
mexsierebis q b s
• yuradRebis gafantvas
kalcineurini axdens NMDA receptoris modulirebas:

11. aregulirebs arxis daxurvas

2. arxis gamtarobis drois Semcirebas

d
ds-iT davadebulebi,
d v de ule
iseve rogorc Ts65Dn virTagvebi
dsku-Si Seicaven genebs,
romlebis asinTezireben
kkalcineurinis
lc eu mainhibirebel
e el
cilebs
bs

21 qromosomis trisomiisas SeimCneva dsku-s

zeeqspresia
q Sesabamisad kalcineurinis
inhibirebis xarjze adgili aqvs
1. NMDAreceptoruli arxebis gaRebis drois
paTlogiuri gazrda,
(rac arxis blokatorebis moxsniT miiRweva)
2. izrdeba arxis gaRebisunarianoba
 mkurnalobis gzebi

• mmag Ts65Dn da Ts1Cje virTagvebis

r bz NMDA
b s modelebze
m
receptoris antagonist MK-801-is moqmedebis Sedegad
NMDA receptorebi zomaze met hiperativobas avlens da
Sesabamisad izrdeba lokomoturi aqtivoba
q (rac
kalcineurinis inhibirebiT aris ganpirobebukli)

• mag Ts65Dn virTagvebis modelebze NMDA receptorebis

antagonist memantinis moqmedebis Sedegad cxovelebs
kkargad
g d umuSavdebaT
u u vde piroiTi refleqsi
efleq SiSzee (romlis
( l
deficitic gaaCniaT ds model Tagvebs, anu igi
aumjobesebs mexsierebisa da daswavlis process am
cxovelebSi)
 adamianis SemTxvevaSi, grZelvadiani
mexsierebis CamoyalibebaSi, CarTuli
unda iyos genebis damatebiTi jgufis
produqtebi.
1. fosforilirebiT,
kerZod adgili aqvs transkrifciis xorcieldeba MAPK–iT
faqtor ELK1-s aqtivaciis regulacias (rac darRveulia TagvebismodelebSi)
ori gziT:

2. sumoilirebiT,
u l e , -
xorcieldeba HSA21qromosomis
erTerTi genis produqtiT
SUMO3-iT (small ubiquitin like modifier protein 3),
(SUMO3-is
SUMO3 s trisomiac
r s m ar
r SeimCneva
S mCn T 65D virTagvebi
Ts65Dn r b )

ELK1 yvelaze kargad Seswavlili

‘mexsierebis’ geni

• MAPK-damokidebuli fosforilireba iwvevs Elk-1is aqtivobis stimulacias

• sumoizaciis Sedegad ELK1-is modifikacia iwvevs mis represias
• MAPK gzis CarTva amcirebs ELK1-is sumoilizacias
normaSi: MAPK is CarTva aaqtivebs Elk-1,
aun zm sas MAPK is
daunizmisas: s moqmedebis
m qm b s gza
za darRveulia,
ar u a amitom
am t m aadgili unda
un a
qondes Elk-1is represias.
 neiroproteqtuli gza

gliis gliis
aqtivoba damokidebuli aqtovoba damokidebuli
neiroproteqtuli neiroproteqtuli
cila (adnc) faqtori (adnf)

NAP SAL
8 aminomJavuri naSTisgan 9 aminomJavuri naSTisgan
Semdgari peptidi Semdgari peptidi
ainhibirebs:
1. β-amiloidisN(Aβ) neirotoqsiurobas
2. amcirebs
c e neiroanTebiTi
e e procesebis
ce e siZlieres
l e e

orive peptidi uzrunvelyobs ds-is neironebis kulturaSi gadarCenas

rac miiRweva maT mier H2O2-isagan
isagan neironebis dacvis xarjze
(anu dacvis es meqsnizmi moicavs dacvas oqsidaciuri stresisgan )
 m rn
mkurnalobis
b s gzebi
z b

fexmZime Ts65Dn virTagvebis NAP da SAL–iT erTdrouli

mkurnalobis Sedegad axaldabadebul trisomul TaobaSi
ar SeimCneoda Seferxebebi ganviTarebis procesSi rig
motorul da sensorul (magram ara yvela) Tvisebebis
mxriv
mxr

es yvelaferi dakavSirebuli unda iyos NMDA da GABA

suberTeulebis Sesabamisi m-rnm-is donis
normalizaciasTan
 oqsidaciuri stresis gza

s s neirodegeneraciis
ds-sas
ds n r n r s procesebs
pr s bs ZiriTadad
Z r
ganapirobebs oqsidaciuri stresis maRali done

genebi, romlebic 21 qromosomazea ganlagebuli da

miekuTvneba oqsidaciuri stresis ganmapirobebel
kandidat genebs:

• SOD1
• APP
• BACH1
 • SOD1 -superoqsid dismutaza;
ROS-is (Jangbadis reqatiuli formebi) damazianebel moqmedebas zRudavs.
misi zeeqspresiisas SeimCneva mexsierebisa da daswavlis deficiti.
dauniT
d u d
daavadebul
v de ul Canasaxis tv
tvinSi misi W
Warbi raodenoba
de iwvevs
wvev
oqsidaciur stress

• Cveulebriv SOD1 Tavisufal

ionebs r qmn s H2O2,
n bs gardaqmnis
romelic detoqsirdeba
katalazas da glutaTion
e q d
peroqsidazas moqmedebiT
q ede
• Cveulebric superoqsid
dismutazas raodenoba
balansSia
l katalazasa
k t l da
d
glutaTion peroqsidazas
raodenobasTan.
• d u
daunis sindromisas,
d , izrdeba
de superoqsid
u e q d dismutazas
d ut raodenoba,
de ,
danarCeni ori fermenti normaSi rCeba, amitom isini veRar
umklavdebian peroqsidis mTliani raodenobis gauvnebelyofas,
el c akumulirdeba
romelic ku ul de ujredSi
uj ed da
d qsovilebSi,
q v le da
d zrdis
d oqsidaciur
q d c u
stress, aCqarebs daberebis process Tavisufali radikalebis
raodenobis gzrdis xarjze
Ts65Dn virTagvebis (arasruli trisomia) gamokvebiT didi
r
raodenobiT
n b m n E-Ti
vitamin E ( n
(antioqsidanti)
qs n ) SeimCneoda
S mCn S m
Semdegi
Sedegebi:

• Semcirda oqsidaciuri stresis markerebis raodenoba da

gaumjobesda maTi daswavlisunarianoba, bazaluri winatvinis
qolinerguli neironebis (bwqn) zomaSi Semcireba aRar
x b
xdeboda, n r n
neironuli zr s
zrdis faqtoris
qt r s r
receptorebis
pt r b s
raodenobis Semcireba bazaluri winatvinis qolinerguli
neironebSi aRar SeimCneoda.

• ds-Ti daavadebul adamianebSi dadginda rom E vitamini

aranair efeqts ar iZleva

• am procesze gavlena unda qondes S100B-cilis trisomias

• Ts65Dn virTagvebSi S100B-cilis masinTezirebeli geni ar

moipoveba, es geni gvxvdeba mxolod MMU10 qromosomaSi

• E vitamini S100B-cilis masinTezirebeli genis trisomiis

SemTxvevaSi efeqts aRar iZleva.
 mkurnalobis gzebi:
• piracetami (mexierebis gaumjobesebisTvis gamoyenebuli wamali)-
ds-is neironul
e ul kulturebSi
kultu e iwvevs
wvev ujredebis
uj ede dacvas
d cv
oqsidaciuri dazianebisagan, (man unda Seamciros ROS done ds
virTagvebSi) da aumjobesebs:

1. mexsierebas

(acetilqolinis funqcionirebis gaadvilebis xarze)

2. daswavlis procesebs
(NMDA receptorze moqmedebis xarjze)

Tumca
u c piracetamis
cet analogiT
l g Ts65Dn vvirTagvebis
gve mkurnaloba
ku l
aranair dadebiT efeqts ar iZleva mexsierebis
gaumjobesebis TvalsazrisiT
 problemebi samizneebis identificirebisa da
farmakoTerapiis preklinikuri Sefaseba

• s HSA21 genebis
dReisaTvis
s n b s Sesaxeb
S s x b informacia
n rm jer
r kidev
limitirebulia, umralevsi genTagani sruliad araa
Seswavlili

• araa yvela is molekuluri meqanizmi gaSifruli

romelTa darRvevasac aqvs adgili trisomiis SemTxvevaSi

• f
farmakoTerapiisTvisYyvelaze
k e v yvel e did
d d problemad
le d rCeba
e
cxovelis srulyofili modelis SerCeva
 gamosavali
g v l ?!

ZuZumwovrebis
u u w v e ujreduli
uj edul kultu
kulturebi
e gvTavazobs
gv v
am problemebis gadaWris rig SesaZleblobebs
SesaZleblobebs::
 1. limfoblastoiduri ujreduli xazis
Seswavla, romelsac iReben ds-iT
daavadebuli pacientebisagan

dadebiTi:
misi kontroli SesaZlebelia
da molekuluri fenotipi
advilad Sesaswavli

uaryobiTi:
igi araa neironuli bunebis

limfoblastebi warmoadgenen
prekursor ujredebs moumwifebeli
limfocitebisaTvis
alternatiuli ujreduli xazis sistemad SeiZleba gamoviyenoT
ganviTarebadi Rerovani ujredebis xazi (iPS), romelsac iReben
genetikuri daavadebis mqone pacientebisagan

igi miiReba adamianis fibroblastebisagan (arapluripotenturi

s m
somaturi
r ujredebi),
r b ) romelic
r m diferencirdeba
r n r b neironuli
n r n tipis
p s
ujredebad

es ujredebi saSualebas gvaZlevs erTdroulad SeviswavloT

noramluri da paTologiuri adamianis qsovilis formireba in
vitro, rac saSualebas gvaZlevs SeviswavloT rogorc
daavadeba, aseve am daavadebis mkurnalobis gzebi

axdenen daunis sindromiT daavadebuli pacientebis

fibroblastebis miRebas, saidanac axdenen adamainis iPC
ujredebis daavadebis specifikuri xazis miRebas
am somatur ujredebSi axdenen Semdegi transkrifciuli
faqtorebis transducirebas: Oct4, Sox2, Klf4 da Myc
ujreduli kulturebi Tavsdeba 2-3 kvira Sesabamis pirobebSi
d de
dadebiTi:
iPS xazis miReba saSualebas gvaZlevs movaxdinoT Seswavla
im ZiriTadi Taviseburebebisa neironebSi, romelic Tan
sdevs
dev preparatis
e t gamoyenebas
g ye e

magaliTad rogoricaa:

• aqsonis ganviTareba,
• pasuxis
u siswrafe
w fe wamlis
w l moqmedebaze
q ede e
• am Tvisebebis cvlileba Sida individebis doneze
• wamliT mkurnalobis Sedegad, ds-is darRvevebis
koreqciis Sesabamisad iPS xazSi SegviZlia ganvsazRvroT
wamlis moqmedebis siZliere da SemdgomSi potenciurad
gamovikvlioT damatebiTi samizneebis arseboba
am anomaliebis ukeT SeswavlisaTvis darRvevebi unda iyos
Seswavlili aramarto genomur doneze da samizneebis
moqmedebis
q ede Sedegad
edeg d darRvevebis
d Rveve kkoreqciisken
eqc ke mimarTuli,
ul ,
aramed cilis donezec

es
s ukanaskneli
n s n moicavs
m s cilebis
b s modificirebas:
m r b s
1. fosforilirebas
2 acetilirebas
2.
3. sumoilizacias

rac cvlis cilebis aqtivobas

es ki myari garanti unda iyos efeqturi
farmakoTerapiisaTvis