• No results found

(2)*35W*)3 JUHHQ RQWKHVXUIDFHRIWKHFHOOERG\DQGSURFHVVHVDQGLQGHQGULWLFVSLQHV

N/A
N/A
Protected

Academic year: 2022

Share "(2)*35W*)3 JUHHQ RQWKHVXUIDFHRIWKHFHOOERG\DQGSURFHVVHVDQGLQGHQGULWLFVSLQHV"

Copied!
78
0
0

Loading.... (view fulltext now)

Full text

(1)

)URP'(3$570(172)&/,1,&$/1(8526&,(1&(

.DUROLQVND,QVWLWXWHW6WRFNKROP6ZHGHQ



*3&5 6 5(*8/$7,1*

&$7(&+2/$0,1(5*,&&(//

6859,9$/$1')81&7,21 

)2&8621*35



(EED*UHJRUVVRQ/XQGLXV





6WRFNKROP









(2)

*35W*)3 JUHHQ RQWKHVXUIDFHRIWKHFHOOERG\DQGSURFHVVHVDQGLQGHQGULWLFVSLQHV

$OOSUHYLRXVO\SXEOLVKHGSDSHUVZHUHUHSURGXFHGZLWKSHUPLVVLRQIURPWKHSXEOLVKHU



3XEOLVKHGE\.DUROLQVND,QVWLWXWHW3ULQWHGE\cWWD7U\FNHUL$%



‹(EED*UHJRUVVRQ/XQGLXV ,6%1

(3)



$%675$&7

'\VIXQFWLRQ DQG G\VUHJXODWLRQ RI FDWHFKRODPLQHUJLF VLJQDOLQJ DUH PDMRU FDXVHV RI PDQ\

QHXURORJLFDO DQG SV\FKLDWULF GLVRUGHUV LQFOXGLQJ 3DUNLQVRQ¶V GLVHDVH 3'  VFKL]RSKUHQLD

$'+' DQG GUXJ DGGLFWLRQ &XUUHQWO\ DQ LQFRPSOHWH XQGHUVWDQGLQJ RI WKH PHFKDQLVPV

UHJXODWLQJWKHIXQFWLRQDQGVXUYLYDORIFDWHFKRODPLQHUJLFQHXURQVKLQGHUVWKHGHYHORSPHQWRI

HIIHFWLYHWUHDWPHQWV&DWHFKRODPLQHUJLFVLJQDOWUDQVPLVVLRQLVHQWLUHO\PHGLDWHGE\*SURWHLQ

FRXSOHG UHFHSWRUV *3&5V  DQG PDQ\ RWKHU *3&5V DUH LQYROYHG LQ WKH UHJXODWLRQ RI

FDWHFKRODPLQHUJLFIXQFWLRQ*3&5VKDYHDQRXWVWDQGLQJSRWHQWLDODVGUXJWDUJHWVDQGWKHZRUN

EHKLQGWKLVWKHVLVZDVWKHUHIRUHIRFXVHGRQLPSURYLQJWKHXQGHUVWDQGLQJRIKRZWZR*3&5V

*35DQG7$$5UHJXODWHWKHVXUYLYDODQGIXQFWLRQRIFDWHFKRODPLQHUJLFFHOOV

2XUPDLQILQGLQJVUHODWHWRWKHHIIHFWVRI*35RQFDWHFKRODPLQHUJLFFHOOVXUYLYDOZLWK

SRWHQWLDO LPSOLFDWLRQV IRU WKH SURJUHVVLRQ RI 3' 'HDWK RI GRSDPLQHUJLF QHXURQV LQ WKH

VXEVWDQWLDQLJUDFDXVHVPDQ\V\PSWRPVLQ3'*35DFFXPXODWHVLQWKHVXEVWDQWLDQLJUDRI

3' SDWLHQWV DQG LV LPSOLFDWHG LQ WKH SDWKRJHQHVLV GXH WR LWV KLJK SURSHQVLW\ WR PLVIROG

DJJUHJDWH DQG WKHUHE\ FDXVH FHOO GHDWK ,Q FRQWUDVW WR WKH QHXURWR[LF *35 DJJUHJDWHV ZH

IRXQGWKDW*35LQWKHSODVPDPHPEUDQHLPSURYHVFHOOXODUUHVLVWDQFHWR3'LQGXFLQJWR[LQV

6KRUWO\ DIWHU WKLV GLVFRYHU\ WKH QHXURWURSKLF DQG QHXURSURWHFWLYH SURWHLQ SURVDSRVLQ 36$3  DQG LWV V\QWKHWLF SHSWLGH GHULYDWLYHV SURVDSWLGHV ZHUH LGHQWLILHG DV DJRQLVWV DW *35 :H

FRXOGFRQILUPELQGLQJRISURVDSWLGHWR*35LQOLYH1DFHOOVEXWQRWLQWHUDFWLRQVRI*35

ZLWKDQRWKHUSURSRVHGSHSWLGHOLJDQGKHDGDFWLYDWRU:HIXUWKHUIRXQGWKDW1DFHOOVVHFUHWH

36$3DQGWKDW*35DWOHDVWLQSDUWPHGLDWHVWKHQHXURWURSKLFHIIHFWVRI36$3LQ1DFHOOV

0RUHRYHU H[WUDFHOOXODU 36$3 SURPRWHV PHPEUDQH DVVRFLDWLRQ RI *35 DQG SDUWLWLRQLQJ RI

*35LQWR*0JDQJOLRVLGHHQULFKHGOLSLGUDIWVZKHUHLWIRUPVFRPSOH[HVZLWK*0/LSLG

UDIWVDUHFUXFLDOIRUWKHQHXURWURSKLFSURSHUWLHVRI36$3DQGSURVDSWLGHVDQG*0WUHDWPHQW

DPHOLRUDWHV WKH SURJUHVVLRQ RI 3' 7KH 36$3LQGXFHG SDUWLWLRQLQJ RI *35 LQWR OLSLG UDIWV

DQGWKHREVHUYHGLQWHUDFWLRQVRI*35ZLWKERWKSURVDSWLGHDQG*0WKXVVXJJHVWWKDWOLSLG

UDIWV SURYLGH D VFDIIROG WKURXJK ZKLFK 36$3 *35 DQG *0 PD\ LQWHUDFW WR LPSURYH

QHXURQDO YLDELOLW\ &ROOHFWLYHO\ WKH UHVXOWV RQ *35 LQGLFDWH WKDW SURPRWLRQ RI *35

GHQVLW\ LQ WKH SODVPD PHPEUDQH versus WKH F\WRSODVP UDWKHU WKDQ DQ RYHUDOO UHGXFWLRQ RI

*35OHYHOVFRXOGGHOD\SURJUHVVLYHGHDWKRIGRSDPLQHUJLFQHXURQV7KH\IXUWKHULGHQWLI\D

SDWKZD\ LQYROYLQJ 36$3 DQG *0 WKDW FRXOG EH WDUJHWHG WR PRGXODWH VRUWLQJ RI *35

EHWZHHQ WKH SODVPD PHPEUDQH DQG WKH F\WRSODVP DQG WR LPSURYH QHXURSURWHFWLYH HIIHFWV RI

*35 )XWXUH VWXGLHV QRZ QHHG WR DGGUHVV WKH PHFKDQLVWLF GHWDLOV RI WKLV SDWKZD\ DQG LWV

UHOHYDQFHWRGRSDPLQHUJLFQHXURQDOVXUYLYDOLQWKHEUDLQ

7$$5PRGXODWHVGRSDPLQHUJLFVLJQDOLQJYLDYDULRXVSDWKZD\VDQGKDVEHHQLPSOLFDWHG

LQQHXURSV\FKLDWULFGLVRUGHUVVXFKDVVFKL]RSKUHQLDELSRODUGLVRUGHUDQG$'+'DVZHOODVLQ

SV\FKRVWLPXODQW DGGLFWLRQ 7KH UHFHSWRU ELQGV DPSKHWDPLQHV LQFOXGLQJ 0'0$ ZLWK KLJK

DIILQLW\+HUHZHIRXQGWKDWJHQHWLFGHOHWLRQRI7$$5LQPLFHHQKDQFHGHIIHFWVRI0'0$RQ

GRSDPLQHUHOHDVHDQGSURGXFWLRQDVZHOODVRQWKHUPRUHJXODWLRQDQGPRWRUEHKDYLRU2YHUDOO

0'0$ DSSHDUHG WR DXWRLQKLELW LWV RZQ DFWLRQV via 7$$5 DQG SRWHQWLDWLRQ RI 7$$5

VLJQDOLQJPD\WKXVEHEHQHILFLDOLQWKHWUHDWPHQWRISV\FKRVWLPXODQWDGGLFWLRQ



 %RWK*35DQG7$$5DUHLQWHUHVWLQJUHFHSWRUVQRWRQO\GXHWRWKHLUUHOHYDQFHWR

GLVHDVH EXW DOVR GXH WR WKHLU XQFRQYHQWLRQDO WUDIILFNLQJ DQG VLJQDOLQJ SURSHUWLHV 7KLV WKHVLV

WKXV SURYLGHV QRYHO LQIRUPDWLRQ RQ *3&5 IXQFWLRQLQJ ZLWK SRWHQWLDO LPSOLFDWLRQV IRU WKH

GHYHORSPHQWRIQRYHOWUHDWPHQWVLQ3'DQGGUXJDGGLFWLRQ

(4)



3238/b59(7(16.$3/,*6$00$1)$771,1*



9DGlUFDWHFKRODPLQHURFKYDUI|UlUGHYLNWLJD"



1HUYFHOOHUNRPPXQLFHUDUPHGYDUDQGUDJHQRPDWWVNLFNDXWROLNDVLJQDOVXEVWDQVHUVRP

ELQGHU WLOO UHFHSWRUHU Sn NULQJOLJJDQGH QHUYFHOOHU *HQRP DWW ROLND QHUYFHOOHU Sn

EHVWlPGDSODWVHULKMlUQDQVNLFNDUXWROLNDVLJQDOVXEVWDQVHURFKKDUROLNDUHFHSWRUHUSn

FHOO\WDQEOLUVLJQDOHULQJHQVSHFLILN'HWWDlUYLNWLJWI|UDWWLQWU\FNRFKVDNHUVRPVNHUL

NURSSHQ VND JH UlWW UHDNWLRQ 3n Vn VlWW OHGHU WLOO H[HPSHO HWW UROLJW VNlPW WLOO DWW MDJ

VNUDWWDUPHQLQWHWLOODWWMDJE|UMDUIOD[DPHGDUPDUQDJUnWDInRQWLK|JHUIRWHQHOOHU

VOLFND PLJ RP PXQQHQ (Q YLNWLJ JUXSS VLJQDOVXEVWDQVHU I|U KMlUQDQV VW\UQLQJ DY

NlQVORU LQOlUQLQJ PLQQH U|UHOVHNRQWUROO PRWLYDWLRQ VWUHVV RFK UlGVOD lU

FDWHFKRODPLQHUQD1lUVLJQDOHULQJHQPHGFDWHFKRODPLQHULQWHIXQJHUDUNDQGHWOHGDWLOO

HWW YLWW VSHNWUXP DY VMXNGRPDU EHURHQGH Sn KXU RFK YDU GHW EOLU IHO 6MXNGRPDU VRP

LQYROYHUDU IHO L FDWHFKRODPLQVLJQDOHULQJ lU WLOO H[HPSHO 3DUNLQVRQV VMXNGRP $'+'

VFKL]RIUHQL GHSUHVVLRQ RFK ELSROlU VMXNGRP 7\YlUU KLQGUDV XWYHFNOLQJHQ DY YlO

IXQJHUDQGH OlNHPHGHO PRW GHVVD VMXNGRPDU DY DWW YL LQWH WLOO IXOOR I|UVWnU KXU

VLJQDOHULQJHQ L GH QHUYFHOOHU VRP VLJQDOHUDU PHG FDWHFKRODPLQHU VW\UV RFK KXU GHUDV

|YHUOHYQDG UHJOHUDV 'HQQD I|UVWnHOVH KDU MDJ I|UV|NW |ND JHQRP DWW VWXGHUD WYn

UHFHSWRUHU *35 RFK 7$$5 'H KlU WYn UHFHSWRUHUQD VYDUDU Sn DQGUD

VLJQDOVXEVWDQVHU lQ FDWHFKRODPLQHU PHQ ILQQV Sn \WDQ WLOO QHUYFHOOHU VRP VlQGHU XW

FDWHFKRODPLQHU RFK SnYHUNDU GHUDV |YHUOHYQDG UHVSHNWLYH VLJQDOHULQJ 9L KDGH GlUI|U

VRP K\SRWHV DWW GHVVD WYn UHFHSWRUHU VNXOOH NXQQD YDUD PnO I|U Q\D OlNHPHGHO L

VMXNGRPDUVRPGUDEEDUFDWHFKRODPLQVLJQDOHULQJHQ



.DQ*35YDUDHWWQ\WWPnOI|UOlNHPHGHOPRW3DUNLQVRQ"



3DUNLQVRQV VMXNGRP lU HQ DOOYDUOLJ QHXURORJLVN VMXNGRP VRP RIWD XSSWlFNV L 

nUVnOGHUQ PHQ L VlOOV\QWD IDOO lYHQ NDQ GUDEED SHUVRQHU Vn WLGLJW VRP L nUVnOGHUQ

6MXNGRPHQOHGHUWLOOVWRUDSUREOHPPHGU|UHOVHI|UPnJDQVnVRPVNDNQLQJDUVYnULJKHWHU

DWWNRQWUROOHUDPRWRULNHQRVWDGLJJnQJOnQJVDPPDU|UHOVHUHOOHUVYnULJKHWHUDWWSnE|UMD

U|UHOVHU 1nJRW VRP XSSPlUNVDPPDWV PHU RFK PHU XQGHU VHQDUH nU lU DWW GH IOHVWD

SDWLHQWHUQD lYHQ GUDEEDV DY SV\NLVND V\PSWRP VnVRP GHSUHVVLRQ V|PQSUREOHP

GHPHQV RFK KDOOXFLQDWLRQHU 0nQJD V\PSWRP L 3DUNLQVRQV VMXNGRP EHURU Sn DWW HQ

VSHFLHOOJUXSSQHUYFHOOHUVRPVLJQDOHUDUPHGFDWHFKRODPLQHQGRSDPLQG|UPHQH[DNW

YDUI|UGHVVDQHUYFHOOHUG|UYHWYLLQWH9LKDUGlUI|UKLWWLOOVLQWHO\FNDWVXWYHFNODQnJRW

OlNHPHGHO VRP I|UKLQGUDU HOOHU VDNWDU QHU VMXNGRPVI|UORSSHW XWDQ NDQ EDUD EHKDQGOD

V\PSWRPHQ 1lU MDJ SnE|UMDGH PLQD GRNWRUVVWXGLHU KDGH PDQ WLWWDW Sn KMlUQRU IUnQ

DYOLGQD 3DUNLQVRQVSDWLHQWHU RFK XSSWlFNW DWW *35 DQVDPODV RFK NOXPSDU LKRS VLJ

LQQH L QHUYFHOOHUQD L GHQ KMlUQUHJLRQ GlU IOHVW GRSDPLQQHUYFHOOHU G|U 6WRUD PlQJGHU

VDPPDQNOXPSDG *35 VnJ PDQ OHGHU WLOO FHOOG|G 0DQ KDGH lYHQ XSSWlFNW DWW

VDPPDQNOXPSQLQJHQEHURUSnDWW*35lUH[FHSWLRQHOOWVYnUI|UFHOOHQDWWSURGXFHUD

RFKGlUI|URIWDUHlQDQGUDUHFHSWRUHUInUIHOIRUPRFKLQWHNDQVNLFNDVWLOOUlWWRPUnGHL

FHOOHQ1lUGHWWDKlQGHULQJULSHUHWWHQ]\PVRPKHWHU3DUNLQRFKPlUNHULQ*35Vn

DWW FHOOHQV QHGEU\WQLQJVPDVNLQHUL NlQQHU LJHQ GH IHODNWLJD UHFHSWRUHUQD RFK I|UVW|U

GHP3UREOHPPHGVWRUDDQVDPOLQJDUXSSVWnUQlU3DUNLQLQWHIXQJHUDUYLONHWlUIDOOHWL

(5)



HQVlUVNLOGW\SDYlUIWOLJ3DUNLQVRQHOOHURPVnP\FNHWIHODNWLJ*35SURGXFHUDVDWW

3DUNLQHOOHUQHGEU\WQLQJVV\VWHPHWLQWHKLQQHUPHG6DPPDQWDJHWYHUNDGHGHWVRPDWW

*35 NXQGH YDUD HQ RUVDN WLOO 3DUNLQVRQ HOOHU nWPLQVWRQH HQ IDNWRU VRP SnVN\QGDU

VMXNGRPVI|UORSSHWRFKPDQWlQNWHGlUI|UDWWPLQVNDGHQLYnHUDY*35ERUGHVN\GGD

PRWVMXNGRPHQ'HWYDUGlUHPRWIRUWIDUDQGHRNODUWYDG*35J|UQlUSURGXNWLRQHQ

DYUHFHSWRUQIXQJHUDUGHQKDPQDULUlWWGHODYFHOOHQRFKJ|UGHWGHQVND

-DJ E|UMDGH PHG DWW In FHOOHU VRP MDJ RGODGH L ODEEHW DWW SURGXFHUD IOXRUHVFHUDQGH

*353nVnVlWWNXQGHMDJI|OMDUHFHSWRUQLPLNURVNRSRFKVHYDUGHQKDPQDURFKKXU

GHQU|UVLJLFHOOHUQD3UHFLVVRPGHQGnYDUDQGHOLWWHUDWXUHQEHVNUHYVnJMDJDWW*35

IUDPI|UDOOWIDQQVLQXWLFHOOHQRFKEDUDLOLWHQXWVWUlFNQLQJYLGFHOO\WDQ 6HILJXU$ 

'lUHPRW YHUNDGH UHFHSWRUHUQD LQWH NOXPSD LKRS VLJ L QnJRQ K|JUH JUDG L GH KlU

FHOOHUQD7LOOPLQI|UYnQLQJXSSWlFNWHMDJRFNVnDWWQlUMDJEHKDQGODGHFHOOHUQDVnDWWGH

EOHYOLNDGRSDPLQQHUYFHOOHUI|UIO\WWDGHVVW|UUHGHOHQDYUHFHSWRUHUQDIUnQFHOOHQVLQVLGD

WLOOFHOO\WDQ 6HILJXU% 'HQW\SDYUHFHSWRUHUVRP*35WLOOK|UEUXNDUEHILQQDVLJ

RFKVLJQDOHUDMXVWYLGFHOO\WDQVnGHWWDW\GGHSnDWWVW|UUHGHOHQDY*35UHFHSWRUHUQD

KDPQDGH Sn UlWW VWlOOH RFK YDU IXQNWLRQHOOD L GH KlU FHOOHUQD 1X XSSVWRG WYn YLNWLJD

IUnJRU DWW EHVYDUD )|U GHW I|UVWD KXU SnYHUNDU *35 FHOOHQV |YHUOHYQDG QlU GHQ

EHILQQHUVLJYLGFHOO\WDQUHVSHNWLYHLQXWLFHOOHQ")|UGHWDQGUDYDGlUGHWVRPJ|UDWW

*35KDPQDUYLGFHOO\WDQ"



)|U DWW XQGHUV|ND KXU *35 NDQ WlQNDV SnYHUND FHOOHQV |YHUOHYQDG L 3DUNLQVRQ

EHKDQGODGHYLFHOOHUQDPHGWUHROLNDJLIWHUVRPG|GDUGRSDPLQQHUYFHOOHURFKVRPNDQ

RUVDND HQ VMXNGRPVELOG VRP VWDUNW OLNQDU 3DUNLQVRQ 9L VnJ Gn DWW GH FHOOHU VRP

SURGXFHUDGH*35RFKKDGHHQK|JDQGHO*35YLGFHOO\WDQGRJLP\FNHWPLQGUH

XWVWUlFNQLQJ lQ FHOOHU VRP LQWH SURGXFHUDGH *35 &HOOHU VRP EDUD KDGH HQ OLWHQ

DQGHO *35 YLG FHOO\WDQ YDU L EHW\GOLJW OlJUH JUDG VN\GGDGH PRW JLIWHUQD 'lUHPRW

NXQGHYLLQWHLQnJRWDYIDOOHQVHDWW*35YDUQHJDWLYI|UFHOOHUQDV|YHUOHYQDGYLONHW

DQWDJOLJHQEHURGGHSnDWWUHFHSWRUQLQWHNOXPSDGHLKRSVLJLGHKlUFHOOHUQD9LYLVVWH

DOOWVnVHGDQWLGLJDUHDWWVDPPDQNOXPSDG*35NDQG|GDQHUYFHOOHU'HQ\DUHVXOWDWHQ

YLVDGHDWWLPRWVDWVWLOOVDPPDQNOXPSDG*35NDQNRUUHNWSURGXFHUDG*35YLG

FHOO\WDQ VN\GGD FHOOHQ 'HW KlU W\GGH Sn DWW PDQ NDQVNH VNXOOH NXQQD VDNWD QHU

FHOOG|GHQ L 3DUNLQVRQ JHQRP DWW I|UVNMXWD I|UGHOQLQJHQ DY *35UHFHSWRUHU IUnQ

FHOOHQVLQVLGDWLOOFHOO\WDQVQDUDUHlQDWWPLQVNDWRWDOQLYnQDY*35LFHOOHQ'HWEOHY

QXlQQXYLNWLJDUHDWWWDUHGDSnYDGVRPQRUPDOWVW\U*35WLOOFHOO\WDQ

Figur 1 



+XUKDPQDU*35YLGFHOO\WDQ"



6WUD[ HIWHU GHQ KlU XSSWlFNWHQ KLWWDGH HQ DQQDQ IRUVNDUJUXSS HQ VLJQDOVXEVWDQV VRP

NXQGHDNWLYHUD*35YLGFHOO\WDQ+HOWLOLQMHPHGGHWMDJKDGHVHWWVnNXQGHGHYLVD

$ %

(6)



DWWDNWLYHULQJDY*35PHGGHQQ\DVLJQDOVXEVWDQVHQOHGGHWLOODWWFHOOHUQDGHMREEDGH

PHGVN\GGDGHVPRWJLIWHWYlWHSHUR[LG6LJQDOVXEVWDQVHQGHKDGHKLWWDWlUHWWNURSSVHJHW

SURWHLQVRPPDQVHGDQWLGLJDUHYHWDWVN\GGDUQHUYFHOOHUQlUGHWIULVlWWVLKMlUQDQ'HW

YHUNDGHQXVRPDWWGHWKlUSURWHLQHWNDOODWSURVDSRVLQHOOHU36$3VN\GGDUQHUYFHOOHU

JHQRPDWWDNWLYHUD*35(IWHUVRPMDJVHWWDWW*35YLGFHOO\WDQVN\GGDGHGHFHOOHU

MDJ MREEDGH PHG XWDQ DWW MDJ WLOOVDWWH QnJRQ VLJQDOVXEVWDQV PLVVWlQNWH MDJ DWW GHVVD

FHOOHUVMlOYDIULVDWWHHQVLJQDOVXEVWDQVVRPDNWLYHUDGHUHFHSWRUQ-DJNXQGHQXWHVWDRP

FHOOHUQDIULVDWWH36$3RFKGHWJMRUGHGH9LGDUHVnJMDJDWWQlUMDJEORFNHUDGH36$3Vn

DWWGHWLQWHNXQGHDNWLYHUD*35PLQVNDGHQLYnHUQDDY*35YLGFHOO\WDQVDPWLGLJW

VRPGH|NDGHLQQHLFHOOHQ 6HILJXU -DJVnJRFNVnDWWFHOOHUQDV|YHUOHYQDGVI|UPnJD

PLQVNDGHHIWHUEORFNHULQJDY36$3'HWKlUYLVDGHDOOWVnDWW36$3I|UXWRPDWWELQGD

WLOORFKDNWLYHUDUHFHSWRUQRFNVnGUDULJnQJHQSURFHVVVRPOHGHUWLOOHQI|UIO\WWQLQJDY

*35WLOOFHOO\WDQ'HWWDE|UEnGH|NDGHSRVLWLYDHIIHNWHUQDDY*35RFKPLQVND

ULVNHQI|UG|GOLJVDPPDQNOXPSQLQJDY*35LQQHLFHOOHQ

Figur 2 



-DJ WLWWDGH lYHQ Sn I|UGHOQLQJHQ DY *35 YLG FHOO\WDQ $QOHGQLQJHQ WLOO GHWWD lU DWW

FHOO\WDQlULQGHODGLHWWVWRUWDQWDOP\FNHWVPnGRPlQHUPHGROLNDVDPPDQVlWWQLQJDY

IHWWHURFKSURWHLQHU(IWHUVRPROLNDW\SHUDYIHWWHURFKROLNDW\SHUDYSURWHLQHUNDQVW\UD

RPRFKKXUUHFHSWRUHUVLJQDOHUDUSnYHUNDVUHFHSWRUQVIXQNWLRQVWDUNWDYYLONHQW\SDY

GRPlQYLGFHOO\WDQGHQEHILQQHUVLJL)|UIO\WWQLQJDYUHFHSWRUHUPHOODQGRPlQHUNDQ

GlUI|U DQYlQGDV DY FHOOHQ I|U DWW UHJOHUD UHFHSWRUHUV DNWLYLWHW Vn DWW GHQ DQSDVVDV WLOO

FHOOHQVEHKRYYLGWLOOIlOOHW0DQKDGHWLGLJDUHVHWWDWWGHVN\GGDQGHHJHQVNDSHUQDKRV

36$3lUEHURHQGHDYDWW36$3EHILQQHUVLJLHQYLVVW\SDYGRPlQHUYLGFHOO\WDQVRP

PDQNDOODUI|UOLSLGUDIWV,QRPGHVVDOLSLGUDIWVlUVlUVNLOWWYnIHWWHU*0RFK*0

YLNWLJDI|U36$3VVN\GGDQGHIXQNWLRQ0HGWDQNHSnDWWDOOWKLWWLOOVW\GGHSnDWWGHWlU

JHQRPDNWLYHULQJDY*35VRP36$3VN\GGDUFHOOHQXQGUDGHMDJRPGHWYDUI|UDWW

*35PnVWHEHILQQDVLJLOLSLGUDIWVI|UDWWIXQJHUDVRPGHVVDYDUVnYLNWLJDI|UGH

VN\GGDQGHHIIHNWHUQDDY36$3-DJIlUJDGHGlUI|ULQFHOOHUQDPHGHWWIOXRUHVFHUDQGH

lPQHVRPEDUDIlUJDU*00DQNXQGHGnVHDWWGHQU|GDIOXRUHVFHQVHQIUnQ*0

$

%

*0 *35 *0*35

DNWLY36$3EORFNHUDG36$3

(7)



LQIlUJQLQJHQRFKGHQJU|QDIOXRUHVFHQVHQIUnQ*35EHIDQQVLJSnVDPPDVWlOOHQSn

FHOO\WDQRFKDWWSnGHVWlOOHQGlUGHWYDUH[WUDP\FNHW*0YDUGHWRFNVnH[WUDP\FNHW

*35 6HILJXU$ 1lUMDJEORFNHUDGH36$3lQGUDGHVGHWKlUP|QVWUHWPDUNDQW

RFKMDJVnJLVWlOOHWDWW*35IUDPI|UDOOWIDQQVLGHGRPlQHUGlUGHWIDQQVP\FNHWOLWH

*0 6H ILJXU  %  9L YLVVWH DOOWVn VHGDQ WLGLJDUH DWW OLSLG UDIWV PHG P\FNHW *0

NUlYVI|UDWW36$3VNDOOVN\GGDFHOOHUQDRFKGHWYLVDGHVLJQXDWW36$3VW\U*35WLOO

GHVVDOLSLGUDIWV

9DGKlQGHULIUDPWLGHQ"



6DPPDQIDWWQLQJVYLVKDUGHWIUDPNRPPLWLVWXGLHUQDNULQJ*35DWWVDPPDQNOXPSDG

*35LQXWLFHOOHQlUWR[LVNPHGDQIXQJHUDQGH*35YLGFHOO\WDQVN\GGDUFHOOHUQD

PRW JLIWHU VRP NDQ RUVDND 3DUNLQVRQ 1HUYFHOOVG|G L 3DUNLQVRQ E|U GlUI|U NXQQD

PRWYHUNDV JHQRP DWW |ND QLYnHUQD DY *35 YLG FHOO\WDQ MlPI|UW PHG LQXWL FHOOHQ

36$3VRPDNWLYHUDU*35VW\URFNVn*35WLOOFHOO\WDQRFKWLOOVSHFLILNDGRPlQHU

LQHKnOODQGH*0LQRPFHOO\WDQVRPlUQ|GYlQGLJDI|U36$3VVN\GGDQGHHJHQVNDSHU

'HWWDW\GHUSnDWW|NDGHQLYnHUDY36$3RFK*0VNXOOHNXQQDYDUDHWWVlWWDWWVW\UD

*35 WLOO FHOO\WDQ RFK WLOO GH GRPlQHU LQRP FHOO\WDQ GlU GHQ KDU HQ VN\GGDQGH

IXQNWLRQ 'HWWD VNXOOH RFNVn In VRP I|OMG DWW QLYnHUQD DY *35 LQXWL FHOOHQ RFK

GlUPHGULVNHQI|UWR[LVNVDPPDQNOXPSQLQJDY*35PLQVNDU0DQNDQRFNVnWlQND

VLJDWWPDQPHGDQGUDVXEVWDQVHUI|UV|NHUKlUPDGHQSURFHVVVRP36$3GUDULJnQJRFK

VRP OHGHU WLOO DWW *35 VW\UV IUnQ FHOOHQV LQVLGD WLOO UlWW VWlOOH YLG FHOO\WDQ (WW

V\QWHWLVNWIUDPVWlOOWlPQHVRPNDQSnYHUNDGHQKlUSURFHVVHQVNXOOHP|MOLJHQYDUDPHU

VSHFLILNW lQ GHQ NURSSVHJQD VLJQDOVXEVWDQVHQ RFK GlUPHG OHGD WLOO IlUUH HYHQWXHOOD

ELYHUNQLQJDU 6|NQLQJ HIWHU VnGDQD V\QWHWLVND VXEVWDQVHU L NRPELQDWLRQ PHG DWW |ND

I|UVWnHOVHQ I|U KXU 36$3 VW\U *35 WLOO FHOO\WDQ lU L PLQ PHQLQJ YLNWLJD PnO I|U

IUDPWLGDVWXGLHU0DQE|UGRFNYDUDPHGYHWHQRPDWWFHOOHURGODGHLHWWODERUDWRULXPlU

OnQJWLIUnQLGHQWLVNDPHGQHUYFHOOHULGHQLQWDNWDKMlUQDQ'HWPnVWHGlUI|UWLOONRPPD

VWXGLHULOHYDQGHGMXURFKVnVPnQLQJRPLSDWLHQWHUI|UDWWYHWDRPGHWYLVHWWKLWWLOOV

VWlPPHU|YHUHQVPHGGHWVRPVNHULKMlUQDQRFKRPGHWNDQDQYlQGDVI|UDWWEHKDQGOD

3DUNLQVRQ'HWlUPHGDQGUDRUGlQQXHQOnQJYlJDWWJnLQQDQYLYHWRPXSSWlFNWHUQD

IUnQ GHQ KlU DYKDQGOLQJHQ NDQ OHGD WLOO IXQJHUDQGH EHKDQGOLQJDU I|U DWW VDNWD QHU

VMXNGRPVI|UORSSHWL3DUNLQVRQ



.DQ7$$5YDUDHWWPnOI|UOlNHPHGHOPRWGURJEHURHQGH"



-DJ KDU lYHQ VWXGHUDW HQ DQQDQ UHFHSWRU 7$$5 VRP UHJOHUDU GRSDPLQQHUYFHOOHUV

VLJQDOHULQJ 6LJQDOHULQJ PHOODQ QHUYFHOOHU VNHU L Vn NDOODGH V\QDSVHU GYV

PHOODQUXPPHWPHOODQDYVlQGDUFHOOHQVXWVNRWWRFKPRWWDJDUFHOOHQXWVNRWW 6HILJXU 

'RSDPLQQHUYFHOOHUIULVlWWHUGRSDPLQWLOOV\QDSVHQLSXOVHUVRPVW\UVDYGHQHOHNWULVND

DNWLYLWHWHQLQHUYFHOOHQ1lUHQGRSDPLQQHUYFHOOlUDNWLYVNLFNDUGHQVQDEEWXWHQYLVV

PlQJG GRSDPLQ VRP VHGDQ VQDEEW WDV WLOOEDND LQ L FHOOHQ PHG KMlOS DY VSHFLHOOD

GRSDPLQWUDQVSRUW|UHU &HOOHQ VNLFNDU VHGDQ XW HQ Q\ ODGGQLQJ GRSDPLQ VRP RFNVn

VQDEEWWDVWLOOEDNDYDUSnGHWKHODXSSUHSDVLJHQ8QGHUGHQNRUWDWLGVRPGRSDPLQHW

EHILQQHUVLJLV\QDSVHQNDQGHWELQGDWLOOUHFHSWRUHUSnPRWWDJDUFHOOHQRFKSnYHUNDGHVV

DNWLYLWHW3nVnVlWWI|UVVLJQDOHQYLGDUHLKMlUQDQVQlWYHUN



(8)



0DQ WURU DWW DPIHWDPLQOLNQDQGH GURJHU IUDPNDOODU EHURHQGH GYV HWW WYnQJVPlVVLJW

LQWDJIUDPI|UDOOWJHQRPDWW|NDIULVlWWQLQJHQDYMXVWGRSDPLQ'HJ|UGHWWDJHQRPDWW

ELQGDWLOORFKEORFNHUDHOOHUWLOORFKPHGlQGUDULNWQLQJHQSnGRSDPLQWUDQVSRUW|UHUQDVn

DWWGRSDPLQHWOLJJHUNYDULV\QDSVHQEHW\GOLJWOlQJUHHIWHUDWWGHWIULVDWWVHOOHUIULVlWWV

WURWVDWWQHUYFHOOHQLQWHlUDNWLY1lUMDJE|UMDGHVWXGHUD7$$5YLVVWHPDQDWWLP|VV

VRP VDNQDU 7$$5 IULVlWWV GRSDPLQ L V\QDSVHQ PHG EHW\GOLJW NRUWDUH LQWHUYDOO lQ

QRUPDOW7$$5NDQDOOWVnPLQVNDGHQWRWDODIULVlWWQLQJHQDYGRSDPLQLKMlUQDQJHQRP

DWW VDNWD QHU VLJQDOHULQJHQV SXOVKDVWLJKHW 0DQ YLVVWH RFNVn DWW DPIHWDPLQ RFK

DPIHWDPLQOLNQDQGHGURJHUNDQELQGDWLOORFKDNWLYHUD7$$51lUGHVVDGURJHUILQQVL

KMlUQDQELQGHUGHDOOWVnEnGHWLOOGRSDPLQWUDQVSRUW|UHUYDUVIXQNWLRQGHKlPPDURFK

WLOO7$$5YDUVIXQNWLRQGHDNWLYHUDU'lUPHGNXQGHPDQYlQWDVLJDWW7$$5VNXOOH

SnYHUNDKXUDPIHWDPLQOLNDQGHGURJHUI|UlQGUDUGRSDPLQIULVlWWQLQJHQ6WXGLHUQDNULQJ

7$$5VRPYLXWI|UGHLVDPDUEHWHPHGIUDQVNDIRUVNDUHJLFNXWSnDWWWDUHGDSnKXU

DNWLYHULQJ DY 7$$5 SnYHUNDU GH HIIHNWHU HFVWDV\ HQ SRSXOlU DPIHWDPLQOLNQDQGH

GURJKDUSnIULVlWWQLQJRFKSURGXNWLRQDYGRSDPLQLKMlUQDQ9LYLOOHRFNVnWLWWDSnKXU

7$$5 SnYHUNDU EHWHHQGHI|UlQGULQJDU NRSSODGH WLOO |NDG GRSDPLQIULVlWWQLQJ L

VDPEDQGPHGHFVWDF\LQWDJ'HWWDJMRUGHVJHQRPDWWEHKDQGODP|VVHOOHUKMlUQYlYQDG

IUnQP|VVPHGHFVWDV\9LMlPI|UGHVHGDQHIIHNWHUQDLP|VVVRP JHQRPHQJHQHWLVN

I|UlQGULQJ LQWH ELOGDU 7$$5 PHG YDQOLJD P|VV I|U DWW VH KXU VLJQDOHULQJ RFK

EHWHHQGHQSnYHUNDVDYMXVW7$$5(WWVlWWDWWPlWDHFVWDV\VSV\NLVNDHIIHNWHULP|VV

lU DWW PlWD |NQLQJHQ L GHUDV U|UHOVHDNWLYLWHW 1lU YnUD VDPDUEHWVSDUWQHUV EHKDQGODGH

P|VV PHG HFVWDV\ VnJ GH DWW P|VVHQ VRP LQWH NXQGH ELOGD 7$$5 EOHY lQQX PHU

K\SHUDNWLYD DY HFVWDV\ lQ YDQOLJD P|VV 'H VnJ RFNVn DWW HFVWDV\ OHGGH WLOO DWW

GRSDPLQIULVlWWQLQJHQ |NDGH PHU L KMlUQDQ Sn P|VVHQ XWDQ 7$$5 lQ L P|VVHQ PHG

7$$5 6DPPDQWDJHW Vn |NDGH DOOWVn GH HIIHNWHU VRP HFVWDV\ KDU Sn

GRSDPLQIULVlWWQLQJ RFK EHWHHQGH QlU P|VVHQ LQWH NXQGH ELOGD 7$$5 (IWHUVRP GHW

IUDPI|UDOOWlU|NDGIULVlWWQLQJDYGRSDPLQVRPOHGHUWLOOEHURHQGHDYDPIHWDPLQOLNDQGH

GURJHUVRPWH[HFVWDV\W\GHUGHWWDSnDWWDNWLYHULQJDY7$$5VNXOOHNXQQDYDUDHWW

VlWWDWWPLQVNDGHEHURHQGHIUDPNDOODQGHHJHQVNDSHUQDVRPGHVVDGURJHUKDU

Figur 3 

+XUSnYHUNDU7$$5SURGXNWLRQHQDYGRSDPLQ"



,QRP GHQ KlU VWXGLHQ XQGHUV|NWH YL L YnUW ODEE KXU 7$$5 SnYHUNDU

GRSDPLQSURGXNWLRQHQLQHUYFHOOHUVRPIULVlWWHUGRSDPLQ7DQNHQEDNRPGHWWDYDUDWW

HQ |NDG SURGXNWLRQ DY GRSDPLQ VDQQROLNW OHGHU WLOO HQ |NDG PlQJG GRSDPLQ VRP

IULVlWWVYLGYDUMHWLOOIlOOH'HWlUPHGDQGUDRUGLQWHEDUDKDVWLJKHWHQI|UIULVlWWQLQJRFK

nWHUXSSWDJ DY GRSDPLQ VRP VW\U VW\UNDQ Sn GRSDPLQVLJQDOHULQJHQ bYHQ PlQJGHQ

WLOOJlQJOLJW GRSDPLQ LQXWL GRSDPLQQHUYFHOOHQ SnYHUNDU VLJQDOHQ 9L VWXGHUDGH GHWWD

JHQRP DWW PlWD DNWLYLWHWHQ KRV GHW HQ]\P VRP VW\U KXU P\FNHW GRSDPLQ VRP

SURGXFHUDV 9L VnJ DWW XWDQ QnJRQ EHKDQGOLQJ DOOV YDU GRSDPLQSURGXNWLRQHQ K|JUH L

(9)



KMlUQYlYQDGIUnQP|VVVRPLQWHKDGH7$$5lQLYlYQDGIUnQYDQOLJDP|VV1lUYL

EHKDQGODGHKMlUQYlYQDGHQPHGHFVWDV\YDUGRSDPLQSURGXNWLRQHQRI|UlQGUDGLYDQOLJD

P|VV PHQ L YlYQDG IUnQ P|VV XWDQ 7$$5 PLQVNDGH GRSDPLQSURGXNWLRQHQ HIWHU

HFVWDV\EHKDQGOLQJHQ 7$$5 KDU DOOWVn WLOO V\QHV PRWVDWWD HIIHNWHU Sn

GRSDPLQSURGXNWLRQ EHURHQGH Sn RP HFVWDV\ ILQQV L KMlUQYlYQDGHQ HOOHU LQWH 'H KlU

UHVXOWDWHQYDUOLWHI|UYnQDQGHPHQGHWILQQVHWWDQWDOP|MOLJDI|UNODULQJDUVRPMDJLQWH

NRPPHUJnLQSnLGHWDOMKlU'HWVRPVWnUNODUWIUnQYnUDVWXGLHUlUDWW7$$5|NDU

GRSDPLQSURGXNWLRQHQGLUHNWPHQlYHQNDQDNWLYHUDDQGUDGHODUDYFHOOHQVRPLVLQWXU

PLQVNDUGRSDPLQSURGXNWLRQHQ9LONHWVRP|YHUYlJHUVW\UVDYKXUP\FNHWGHWILQQVDY

ROLND DQGUD PROHN\OHU L FHOOHQ YLG MXVW GHW WLOOIlOOHW 7$$5 YHUNDU YDUD HQ GHO L HWW

JDQVND NRPSOLFHUDW QlWYHUN DY VLJQDOHULQJVPROHN\OHU L GRSDPLQQHUYFHOOHQ VRP DOOD

SnYHUNDU GRSDPLQSURGXNWLRQHQ 'HW lU P|MOLJW DW 7$$5 EDODQVHUDU SURGXNWLRQHQ

EHURHQGHSn|YULJDRPVWlQGLJKHWHUI|UDWWDQSDVVDGHQWLOOFHOOHQVEHKRYPHQI|UDWW

XWUHGDGHWKlURUGHQWOLJWNUlYVGHWPnQJDIOHUH[SHULPHQWVRPI|UV|NHUWDUHGDSnKXU

GHW KlU QlWYHUNHW LQXWL FHOOHQ lU VDPPDQNRSSODW )|U HFVWDV\ LQQHElU YnUD UHVXOWDW DWW

lYHQRPHFVWDV\YLD7$$5LVWRUWPRWYHUNDUVLQDHJQDHIIHNWHUSnGRSDPLQVLJQDOHULQJ

VH VW\FNHW RYDQ  Vn JlOOHU GHWWD LQWH I|U MXVW SURGXNWLRQHQ DY GRSDPLQ $WW 7$$5

HYHQWXHOOW EDODQVHUDU GRSDPLQSURGXNWLRQHQ NDQ GlUHPRW YLVD VLJ YDUD UHOHYDQW L

I|UVWnHOVHQRFKEHKDQGOLQJHQDYDQGUDVMXNGRPVWLOOVWnQGGlUGRSDPLQVLJQDOHULQJHQLQWH

IXQJHUDUVnVRPVFKL]RIUHQLRFKELSROlUVMXNGRP+lUNUlYVGHWGRFNPnQJDIOHURFK

PHUGHWDOMHUDGHVWXGLHUDYHIIHNWHUQDDY7$$5SnGRSDPLQQHUYFHOOHULQQDQPDQNDQ

GUDQnJUDW\GOLJDVOXWVDWVHU'HHIIHNWHUYLVnJDY7$$5SnSURGXNWLRQHQDYGRSDPLQ

JDYRVVPHGDQGUDRUGHWWDQWDOQ\DIUnJRUDWWEHVYDUDRFKInHQW\GLJDVYDU



9LONDP|MOLJKHWHURFKVYnULJKHWHUVWnUYLLQI|UQX"



6DPPDQIDWWQLQJVYLV NDQ HFVWDV\ JHQRP DNWLYHULQJ DY 7$$5 VMlOY UHGXFHUD GHQ

|NQLQJ DY GRSDPLQIULVlWWQLQJ RFK GH EHWHHQGHHIIHNWHU VRP GURJHQ RUVDNDU YLD

GRSDPLQWUDQVSRUW|UHUQD(IWHUVRPMXVWHIIHNWHUQDSnGRSDPLQVLJQDOHULQJlUYLNWLJDI|U

GHVV EHURHQGHIUDPNDOODQGH HJHQVNDSHU W\GHU GHWWD Sn DWW HQ |NDG DNWLYHULQJ DY

7$$5 VNXOOH NXQQD PRWYHUND EHURHQGH DY HFVWDV\ RFK DQGUD DPIHWDPLQOLNDQGH

GURJHU )|U DWW XWUHGD GHWWD YLGDUH PnVWH PDQ QX WLWWD Sn YDG VRP KlQGHU PHG DNWLYW

LQWDJ DY HFVWDV\ L P|VV VRP VDNQDU 7$$5 DOWHUQDWLYW P|VV PHG HQ |NDG 7$$5

DNWLYLWHWMlPI|UWPHGQRUPDODP|VV2PP|VVHQVMlOYDInUWDHFVWDV\LVWlOOHWI|UDWWEOL

LQMLFHUDGHPHGHFVWDV\WDUGHGnPHURPGHVDNQDU7$$5RFKPLQGUHRP7$$5

DNWLYLWHWHQ |NDU" 5HVXOWDWHQ KLWWLOOV W\GHU Sn DWW Vn ERUGH YDUD IDOOHW PHQ GHW PnVWH

EHNUlIWDVPHGH[SHULPHQWVRPWLWWDUSnGHWWDVSHFLILNW



'H HIIHNWHU 7$$5 KDU Sn GRSDPLQSURGXNWLRQHQ NUlYHU HQ KHO GHO YLGDUH XWUHGQLQJ

LQQDQYLNDQGUDQnJUDVOXWVDWVHUNULQJGHVVUHOHYDQVI|UGURJEHURHQGHRFKSV\NLDWULVND

VMXNGRPDU(QYLNWLJDVSHNWDWWWDPHGLEHUlNQLQJHQQlUGHWJlOOHU7$$5VRPPnO

I|UOlNHPHGHOLDOOPlQKHWlURFNVnDWW7$$5LQWHEDUDILQQVLKMlUQDQ7$$5ILQQV

EODQGDQQDWLKMlUWPXVNHOQRFKLFHOOHUVRPWLOOK|ULPPXQI|UVYDUHW2PPDQDNWLYHUDU

7$$5NDQPDQGlUI|UXW|YHUGHHIIHNWHUVRPEHVNULYLWVKlUInHIIHNWHUSnKMlUWDWRFK

LPPXQI|UVYDUHW 'HW ILQQV GlUPHG VWRUD ULVNHU I|U DOOYDUOLJD ELYHUNQLQJDU DY DWW

DNWLYHUD 7$$5 'HVVD ULVNHU PnVWH PDQ XWUHGD QRJJUDQW I|U DWW YDUD VlNHU Sn DWW

HYHQWXHOOD IUDPWLGD EHKDQGOLQJDU ULNWDGH PRW 7$$5 lU VSHFLILND RFK QnJRUOXQGD

ULVNIULD

(10)



/,672)38%/,&$7,216

, *UHJRUVVRQ/XQGLXV(6WURWK19XNRMHYLü97HUHQLXV/6YHQQLQJVVRQ3

)XQFWLRQDO*5WUDIILFNLQJSURWHFWVDJDLQVWWR[LFLW\LQGXFHGE\

2+'$033RUURWHQRQHLQDFDWHFKRODPLQHUJLFFHOOOLQH

Journal of Neurochemistry 2013; 124: 410-417

,, *UHJRUVVRQ/XQGLXV(9XNRMHYLü96WURWK17HUHQLXV/6YHQQLQJVVRQ3

*35WUDIILFNLQJWRWKHSODVPDPHPEUDQHUHJXODWHGE\SURVDSRVLQDQG

*0JDQJOLRVLGHVSURPRWHVFHOOYLDELOLW\

Journal of Biological Chemistry, under revision ,,, *UHJRUVVRQ/XQGLXV(9XNRMHYLü96YHQQLQJVVRQ3

+HDGDFWLYDWRUGRHVQRWELQGWR*35LQOLYH1DFHOOV

Manuscript

,9 'L&DUD%0DJJLR0$ORLVL*5LYHW-0*UHJRUVVRQ/XQGLXV(<RVKLWDNH

76YHQQLQJVVRQ3%URFFR0*REHUW$'H*URRWH/&LVWDUHOOL/9HLJD6

'H0RQWULRQ&5RGULJXH]0*DOL]]L-3/RFNKDUW%3&RJp)%RXWLQ-$

9D\HU39HUGRXZ30*URHQLQN/0LOODQ0-

*HQHWLFGHOHWLRQRIWUDFHDPLQHUHFHSWRUVUHYHDOVWKHLUUROHLQDXWR

LQKLELWLQJWKHDFWLRQVRIHFVWDV\ 0'0$ 

Journal of Neuroscience 2011; 31(47): 16928-16940













$GGLWLRQDO3XEOLFDWLRQ'XULQJ3K'6WXGLHV



<DQJ-*UHJRUVVRQ/XQGLXV(=KDQJ;&HGHUOXQG$/L-6YHQQLQJVVRQ3

5ROHVRIUHGXFHGJOXFRFHUHEURVLGDVHDFWLYLW\DQGLQFUHDVHGJOXWDPDWH10'$

UHFHSWRUIXQFWLRQDOLW\LQQHXURWR[LFDFWLRQVRIĮV\QXFOHLQ

Manuscript submitted to Neurochemistry International

(11)



&217(176

 ,QWURGXFWLRQ

 *SURWHLQFRXSOHGUHFHSWRUV *3&5V 

 &DWHFKRODPLQHUJLFIXQFWLRQLQWKHFHQWUDOQHUYRXVV\VWHP

 &HQWUDOFDWHFKRODPLQHUJLFQHWZRUNV

 0HGLDWRUVRIFDWHFKRODPLQHUJLFVLJQDOLQJ

 3DUNLQVRQ¶VGLVHDVH

 3DWKRJHQHVLV

 ([SHULPHQWDO0RGHOV

 *35

 6WUXFWXUHKRPRORJ\DQGH[SUHVVLRQSURILOH

 5ROHLQSDWKRJHQHVLVRI3DUNLQVRQ¶VGLVHDVH

 3URSRVHGOLJDQGV

 3V\FKRVWLPXODQWDFWLRQVDWFDWKHFRODPLQHUJLFQHXURQV

 $PSKHWDPLQHDQGLWVGHULYDWLYHV

 7$$5

 $LPV

 0HWKRGRORJLFDOFRQVLGHUDWLRQV

 0HDVXULQJFHOOYLDELOLW\DQGFHOOGHDWK

 )OXRUHVFHQFHFRUUHODWLRQDQGFURVVFRUUHODWLRQVSHFWURVFRS\

 5HVXOWVDQGGLVFXVVLRQ

 )XQFWLRQDO*35UHJXODWHVFDWHFKRODPLQHUJLFFHOOVXUYLYDO

 *HQHUDWLRQRIDsWDEOHFHOOOLQHH[SUHVVLQJIXQFWLRQDOO\

WUDIILFNHG*35

 *35LQWKHSODVPDPHPEUDQHSURWHFWVDJDLQVWWR[LFLW\

 3URVDSWLGHEXWQRWKHDGDFWLYDWRUELQGVWR*35

 3URVDSRVLQSURPRWHVVXUIDFHGHQVLW\RI*35

 3URVDSRVLQSURPRWHVVRUWLQJRI*35WROLSLGUDIWV

 3URVDSRVLQSURPRWHVFHOOYLDELOLW\YLD*35

 *35LVIRXQGLQO\VRVRPHVEXWQRWLQPLWRFKRQGULD

 7$$5PRGXODWHVHIIHFWVRI0'0$RQFDWHFKRODPLQHIXQFWLRQ

 7$$5DFWLYDWLRQE\0'0$LQFUHDVHVW\URVLQHK\GUR[\ODVH

SKRVSKRU\ODWLRQDQGDFWLYLW\

 &RQFOXGLQJUHPDUNV

 &RQFOXVLRQV

 3RWHQWLDOIXWXUHVWXGLHV

 $FNQRZOHGJHPHQWV

 5HIHUHQFHV



(12)



/,672)$%%5(9,$7,216



$'+'

$3'

$5-3

$73

ȕ3($

F$03

&16

&207

&5(%

&7[%

'$7

GEF$03

(5

(5$'

)&&6

)&6

)5$3

)5(7

*3&5

*5.

*67

+$

+VS

.2

/$$'&

/'+

0$2$

0$2%

Pȕ&'

0'0$

033

0333

0373

PW'1$

077

1(7

2+'$

3&$

3'

3.$

3.&

3/$

DWWHQWLRQGHILFLWK\SHUDFWLYLW\GLVRUGHU

DYDODQFKHSKRWRGLRGH

DXWRVRPDOUHFHVVLYHMXYHQLOH3DUNLQVRQ¶VGLVHDVH

DGHQRVLQHWULSKRVSKDWH

ȕSKHQ\OHWK\ODPLQH

F\FOLFDGHQRVLQHPRQRSKRVSKDWH

FHQWUDOQHUYRXVV\VWHP

FDWHFKRODPLQH2PHWK\OWUDQVIHUDVH

F$03UHVSRQVHHOHPHQWELQGLQJSURWHLQ

FKROHUDWR[LQȕVXEXQLW

GRSDPLQHWUDQVSRUWHU

GLEXW\U\OF$03

HQGRSODVPLFUHWLFXOXP

(5DVVRFLDWHGGHJUDGDWLRQ

IOXURUHVFHQFHFURVVFRUUHODWLRQVSHFWURVFRS\

IOXRUHVFHQFHFRUUHODWLRQVSHFWURVFRS\

IOXRUHVFHQFHUHFRYHU\DIWHUSKRWREOHDFKLQJ

IOXRUHVFHQFHUHVRQDQFHHQHUJ\WUDQVIHU

*SURWHLQFRXSOHGUHFHSWRU

*3&5NLQDVH

JOXWDWKLRQH6WUDQVIHUDVH

KHDGDFWLYDWRU

KHDWVKRFNSURWHLQ

NQRFNRXW

/DURPDWLFDPLQRDFLGGHFDUER[\ODVH

ODFWDWHGHK\GURJHQDVH

PRQRDPLQHR[LGDVH$

PRQRDPLQHR[LGDVH%

PHWK\OȕF\FORGH[WULQ

PHWK\OHQHGLR[\PHWDPSKHWDPLQH

PHWK\OSKHQ\OS\ULGLQLXP

PHWK\OSKHQ\OSURSLRQR[\SLSHULGLQH

PHWK\OSKHQ\OWHWUDK\GURS\ULGLQH

PLWRFKRQGULDO'1$

 GLPHWK\OWKLD]RO\O GLSKHQ\OWHWUD]ROLXPEURPLGH

QRUHSLQHSKULQHWUDQVSRUWHU

K\GUR[\GRSDPLQH

SDUDFKORURDPSKHWDPLQH

3DUNLQVRQ¶VGLVHDVH

SURWHLQNLQDVH$

SURWHLQNLQDVH&

SKRVSKROLSDVH$

(13)

 36$3

367; $  5K*

526

516

6DS

6'63$*(

61

61SF

7$05$

W*)3

7+

781(/

835

90$7

97$

:7





























































SURVDSRVLQ

SURVDSWLGH7; $  UKRGDPLQH*

UHDFWLYHR[\JHQVSHFLHV

UHDFWLYHQLWURJHQVSHFLHV

VDSRVLQ

VRGLXPGRGHF\OVXOSKDWHSRO\DFU\ODPLGHJHOHOHFWURSKRUHVLV

VXEVWDQWLDQLJUD

VXEVWDQWLDQLJUDSDUVFRPSDFWD

FDUER[\WHWUDPHWK\OUKRGDPLQH

WXUERJUHHQIOXRUHVFHQWSURWHLQ

W\URVLQHK\GUR[\ODVH

WHUPLQDOWUDQVIHUDVHPHGLDWHGG873QLFNHQGODEHOLQJ

XQIROGHGSURWHLQUHVSRQVH

YHVLFXODUPRQRDPLQHWUDQVSRUWHU

YHQWUDOWHJPHQWDODUHD

ZLOGW\SH



(14)





(15)

  

 ,1752'8&7,21

6LQFH WKH LQLWLDO PDSSLQJ RI FDWHFKRODPLQHUJLF QHXURQV LQ WKH EUDLQ &DUOVVRQ HW DO

'DKOVWURHP )X[H LWKDVEHFRPHFOHDUWKDWFDWHFKRODPLQHUJLFVLJQDOLQJ

LVLQYROYHGLQDYDULHW\RIQHXURQDOIXQFWLRQV)XQFWLRQVUHJXODWHGE\FDWHFKRODPLQHUJLF

VLJQDOLQJ LQFOXGH PRWRU FRQWURO PRRG UHZDUG PRWLYDWLRQ VWUHVV IHDU OHDUQLQJ DQG

PHPRU\ &RQVHTXHQWO\ G\VIXQFWLRQ RI FDWHFKRODPLQHUJLF QHWZRUNV FDQ OHDG WR D

PXOWLWXGH RI VHYHUH QHXURORJLFDO DQG SV\FKLDWULF GLVRUGHUV VXFK DV VFKL]RSKUHQLD

GHSUHVVLRQ $'+' ELSRODU GLVRUGHU DQG 3DUNLQVRQ¶V GLVHDVH &XUUHQW WUHDWPHQWV

DJDLQVWWKHVHGLVRUGHUVDUHXQVDWLVIDFWRU\ZLWKPDLQO\V\PSWRP PDQDJLQJHIIHFWVEXW

QR GLVHDVH PRGLI\LQJ SURSHUWLHV ODUJH JURXSV RI QRQUHVSRQGHUV DQGRU KLJKO\

GHELOLWDWLQJVLGHHIIHFWV0DQ\SV\FKRDFWLYHGUXJVDOVRWDUJHWFDWHFKRODPLQHUHFHSWRUV

RU WUDQVSRUWHUV DQG LPSURYHG WUHDWPHQWV RI GUXJ DGGLFWLRQ DUH KLJKO\ QHHGHG ,W LV

WKHUHIRUHSUHVVLQJWRLPSURYHRXUXQGHUVWDQGLQJRIWKHFDWHFKRODPLQHUJLFV\VWHPVDQG

KRZWKH\DUHUHJXODWHGLQKHDOWKDQGGLVHDVH



$OO FDWHFKRODPLQH UHFHSWRUV DUH * SURWHLQFRXSOHG UHFHSWRUV *3&5V  DQG

VHYHUDO DGGLWLRQDO *3&5V DUH LQYROYHG LQ PRGXODWLQJ FDWHFKRODPLQHUJLF IXQFWLRQ

*3&5V FRPSULVH WKH ODUJHVW IDPLO\ RI WUDQVPHPEUDQH UHFHSWRUV 5RVHQEDXP HW DO

  DQG DUH WDUJHWV RI DERXW  RI DOO FXUUHQW WKHUDSHXWLF DJHQWV %ULGJHV  /LQGVOH\ 'XHWRWKHLUKLJKVLJQDOVSHFLILFLW\DQGWKHLUDELOLW\WREHDFWLYDWHGE\

VPDOOPROHFXOHV VXFKDVKRUPRQHVQHXURWUDQVPLWWHUVSHSWLGHVDQGOLSLGV *3&5VDUH

OHDGLQJWDUJHWVIRUQHZWKHUDSHXWLFVDJDLQVWDYDULHW\RIFRQGLWLRQVLQFOXGLQJGLVRUGHUV

RIWKHFDWHFKRODPLQHV\VWHPVIRUZKLFKPRUHHIIHFWLYHWUHDWPHQWVDUHVWLOOQHHGHG7KH

VWXGLHVGHVFULEHGLQWKLVWKHVLVZHUHIRFXVHGRQHOXFLGDWLQJWKHIXQFWLRQRIWZR*3&5V

*35DQG7$$5ZKLFKKDYHEHHQUHSRUWHGWRSOD\LPSRUWDQWUROHVLQWKHVXUYLYDO

DQG VLJQDOLQJ RI FDWHFKRODPLQHUJLF FHOOV ZLWK OLQNV WR 3' SV\FKRVWLPXODQW DGGLFWLRQ

DQGQHXURSV\FKLDWULFGLVRUGHUV



 *3527(,1&283/('5(&(37256 *3&56 

$OO*3&5VFRQWDLQĮKHOLFDOWUDQVPHPEUDQHGRPDLQVHDUQLQJWKHPWKHDOWHUQDWLYH

QDPH 70 UHFHSWRUV 7KH WUDQVPHPEUDQH KHOLFHV DUH FRQQHFWHG E\ VL[ DOWHUQDWLQJ

LQWUDFHOOXODU DQG H[WUDFHOOXODU ORRSV DQG DOO *3&5V KDYH DQ 1WHUPLQDO H[WUDFHOOXODU

GRPDLQDQGD&WHUPLQDOLQWUDFHOOXODUWDLO )LJ$ 7UDGLWLRQDOO\LQWUDFHOOXODU*3&5

VLJQDO WUDQVGXFWLRQ ZDV WKRXJKW WR RQO\ RFFXU WKURXJK FRXSOLQJ RI WKH UHFHSWRUV WR

GLIIHUHQW KHWHURWULPHULF *SURWHLQV )LJ  %  %ULGJHV  /LQGVOH\   7KH *

SURWHLQVLQWHUDFWZLWKWKH&WHUPLQDOWDLORIWKHUHFHSWRUDQGDFKDQJHRIWKH*3&5LQWR

LWVDFWLYHFRQIRUPDWLRQOHDGVWRGLVVRFLDWLRQRIWKH*ĮVXEXQLWIURPWKH*ȕȖVXEXQLWV

7KLVLV IROORZHGE\DFWLYDWLRQ RULQKLELWLRQ RIVHFRQG PHVVHQJHUV E\WKH*ĮVXEXQLW

)RU H[DPSOH *ĮV VXEXQLWV DFWLYDWH DGHQ\ODWH F\FODVH *ĮLR VXEXQLWV LQKLELW DGHQ\ODWH

F\FODVH DQG *ĮT VXEXQLWV DFWLYDWH SKRVSKROLSDVH & 7KHVH FKDQJHV LQ WXUQ OHDG WR D

YDULHW\RIGRZQVWUHDPHIIHFWVRQFHOOXODUIXQFWLRQ



'XULQJWKHODVWGHFDGHLWKDVKRZHYHUEHFRPHFOHDUWKDW*3&5VLJQDOV DUHQRW

RQO\FRQYH\HGE\WKH*ĮVXEXQLWV7KHLQWUDFHOOXODUGRPDLQVRI*3&5VGLUHFWO\LQWHUDFW

ZLWK D SOHWKRUD RI SURWHLQV RI ZKLFK VRPH FRQYH\ VLJQDOV WKURXJK ODUJH LQWHJUDWHG

QHWZRUNV 5LWWHU +DOO 0RVWQRWDEO\ȕDUUHVWLQV )LJ& DQG*3&5NLQDVHV

(16)



*5.  ZKLFK ZHUH SUHYLRXVO\ WKRXJKW WR RQO\ EH LQYROYHG LQ GHVHQVLWL]DWLRQ DQG

LQWHUQDOL]DWLRQ RI *3&5V SOD\ DQ LPSRUWDQW UROH LQ * SURWHLQ LQGHSHQGHQW VLJQDO

WUDQVGXFWLRQ 5DMDJRSDO HW DO  5HLWHU HW DO   *3&5 VLJQDOLQJ WKURXJK ȕ

DUUHVWLQV DQG *5.V FDQ WULJJHU QXPHURXV LQWUDFHOOXODU VLJQDOLQJ FDVFDGHV DQG DIIHFW

FHOOXODU IXQFWLRQV DV GLYHUVH DV DSRSWRWLFDQWLDSRSWRWLF VLJQDOV JHQH WUDQVFULSWLRQ

SURWHLQ V\QWKHVLV DQG FKHPRWD[LV 5DMDJRSDO HW DO  5HLWHU HW DO   7KH

GLVFRYHU\RI*SURWHLQLQGHSHQGHQWVLJQDOLQJRSHQHGXSWKHILHOGRIELDVHGDJRQLVP,W

LV QRZ ZHOO HVWDEOLVKHG WKDW HDFK *3&5 FDQ WDNH RQ D QXPEHU RI GLVWLQFW DFWLYH

FRQIRUPDWLRQV 5HLWHU HW DO   %LDVHG DJRQLVWV RQO\ WULJJHU D VXEVHW RI WKHVH

FRQIRUPDWLRQVDQGWKXVRQO\DFWLYDWHDVXEVHWRIWKHLQWUDFHOOXODUFDVFDGHVWKDWFDQEH

WULJJHUHGE\WKHUHFHSWRU 5HLWHUHWDO 6RPHDJRQLVWVWKXVKDYHDELDVWRZDUGV

FHUWDLQVLJQDOLQJSDWKZD\VZKHUHDVRWKHUXQELDVHGDJRQLVWVFDQLQGXFHWKHIXOOUDQJH

RIVLJQDOLQJFDVFDGHVWKDWPD\EHWULJJHUHGE\WKHERXQG*3&5



 

 

.QRZOHGJHRQ*3&5WUDIILFNLQJLVDOVRH[SDQGLQJ7KHWUDGLWLRQDOYLHZZDVWKDW

*3&5VDIWHUDFWLYDWLRQDUHSKRVSKRU\ODWHGE\*5.VZKLFKOHDGVWRUHFUXLWPHQWRIȕ

DUUHVWLQDQGVXEVHTXHQWUHFHSWRUGHVHQVLWL]DWLRQDQGFODWKULQGHSHQGHQWLQWHUQDOL]DWLRQ

&XUUHQWO\ KXQGUHGV RI DGGLWLRQDO DGDSWRU SURWHLQV DUH NQRZQ WKDW UHJXODWH YDULRXV

DVSHFWV RI *3&5 WUDIILFNLQJ VXFK DV PHPEUDQH DQFKRULQJ H[RF\WRVLV HQGRF\WRVLV

WUDIILFNLQJ WR O\VRVRPHV DQG UHF\FOLQJ WR WKH SODVPD PHPEUDQH %MRUN  6YHQQLQJVVRQ5LWWHU +DOO /LSLGVDUHDOVRNQRZQWRSOD\DQLPSRUWDQW

UROHLQWKHUHJXODWLRQRI*3&5IXQFWLRQDQGWUDIILFNLQJ %MRUN 6YHQQLQJVVRQ 

&HOOXODU PHPEUDQHV FRQWDLQ KLJKO\ VWUXFWXUHG PLFURGRPDLQV FDOOHG OLSLG UDIWV ZKLFK

DUH HQULFKHG LQ VDWXUDWHG OLSLGV VXFK DV FKROHVWHURO FHUDPLGHV VSKLQJRP\HOLQ

JO\FRVSKLQJROLSLGV RU JDQJOLRVLGHV /LQJZRRG  6LPRQV   /LSLG UDIWV DUH

G\QDPLF XQLWV ZKRVH FRPSRVLWLRQ DQG VL]H FDQ YDU\ GHSHQGLQJ RQ WKH OLSLG DQG

SURWHLQ FRQWHQW RI WKH PHPEUDQH DV ZHOO DV LQIOXHQFHV IURP WKH F\WRVNHOHWRQ DQG

ROLJRPHUL]DWLRQ RI UDIW OLSLGV DQG SURWHLQV &KLDQWLD  /RQGRQ  6LPRQV  Figure 1: *3&5 VWUXFWXUH

DQG VLJQDOLQJ $  *HQHUDO

VWUXFWXUH RI D *3&5 %  6FKHPDWLF GUDZLQJ RI

FDQRQLFDO *3&5 VLJQDOLQJ

&  ,QLWLDO VWHSV RI WKH PRVW

ZHOO FKDUDFWHUL]HG ȕDUUHVWLQ

LQGXFHGVLJQDOLQJSDWKZD\V

(17)

  

6DPSDLR +HQFHOLSLGUDIWVFDQVHSDUDWHRUFOXVWHUSURWHLQVLQFOXGLQJ*3&5V

LQDFHOODQGDFWLYLW\VSHFLILFPDQQHUDQGGLUHFWWKHLQWUDFHOOXODUIDLWKRIHQGRF\WRVHG

UHFHSWRUV &KLDQWLD  /RQGRQ  6LPRQV  6DPSDLR   0RUHRYHU VRPH

*3&5V ZHUH UHFHQWO\ IRXQG WR KDYH VSHFLILF FKROHVWHURO ELQGLQJ VLWHV ZKRVH

LQWHUDFWLRQVZLWKFKROHVWHUROGHWHUPLQHUHFHSWRUFRQIRUPDWLRQDQGDFWLYLW\ +DQVRQHW

DO3DLOD &KDWWRSDGK\D\ 



'LVWLQFW LQWUDFHOOXODU FRXSOLQJ GHWHUPLQHG E\ WKH UHFHSWRU¶V SULPDU\ DQG

VHFRQGDU\VWUXFWXUHROLJRPHUL]DWLRQVWDWHWKHVSHFLILFFRQIRUPDWLRQDOFKDQJHWULJJHUHG

E\ D FHUWDLQ OLJDQG DQG WKH OLSLG DQG SURWHLQ FRPSRVLWLRQ RI WKH UHFHSWRU¶V

PLFURHQYLURQPHQW LQ WKH PHPEUDQH FRQIHUV D KLJK OHYHO RI VLJQDO VSHFLILFLW\ IRU

*3&5V,QDGGLWLRQPDQ\*3&5VDQGWKHLULQWHUDFWLQJSURWHLQVGLVSOD\GLVFUHWHWLVVXH

GLVWULEXWLRQV FRQIHUULQJ WLVVXH VSHFLILFLW\ RI V\VWHPLFDOO\ DYDLODEOH OLJDQGV 7KLV KLJK

VLJQDODQGWLVVXHVSHFLILFLW\LVWKHPDLQUHDVRQIRUWKHKLJKSRWHQWLDORI*3&5VDVGUXJ

WDUJHWV DQG WKH SDUWLFXODU LQWHUHVW WKDW WKH\ DWWUDFW LQ UHVHDUFK DLPLQJ DW LPSURYHG

WUHDWPHQWVRIQHXURORJLFDODQGQHXURSV\FKLDWULFGLVRUGHUV



 &$7(&+2/$0,1(5*,& )81&7,21 ,1 7+( &(175$/ 1(59286

6<67(0

&DWHFKRODPLQHV DUH VPDOO

QHXURWUDQVPLWWHUV SURGXFHG

IURP WKH VDPH DPLQR DFLG

SUHFXUVRU W\URVLQH )LJ  

,Q  &DUOVVRQ )DOFN DQG

+LOODUS &DUOVVRQHWDO 

ILUVW PDSSHG WKH

FDWHFKRODPLQHV ZKLFK

LQFOXGH GRSDPLQH

QRUHSLQHSKULQH

QRUDGUHQDOLQ  DQG

HSLQHSKULQH DGUHQDOLQ  LQ

WKH FHQWUDO QHUYRXV V\VWHP

&16  6LQFH WKHQ LW KDV

EHFRPH FOHDU WKDW

FDWHFKRODPLQHUJLF QHXURQV

SOD\ FHQWUDO UROHV LQ WKH

UHJXODWLRQ RI D ODUJH YDULHW\

RIEUDLQIXQFWLRQV







Figure 2: &DWHFKRODPLQH

VWUXFWXUHV DQG HQ]\PHV

LQYROYHGLQWKHLUV\QWKHVLVIURP

WKH DPLQR DFLG SUHFXUVRU

W\URVLQH



(18)



 &HQWUDO&DWHFKRODPLQHUJLF1HWZRUNV

7KHILUVWGHWDLOHGGHVFULSWLRQRIWKHGLVWULEXWLRQRIFDWHFKRODPLQHUJLFQHXURQVLQWKHUDW

&16 ZDV SXEOLVKHG LQ  'DKOVWURHP  )X[H   'DKOVWU|P DQG )X[H WKHQ

LGHQWLILHGWZHOYHJURXSVRIFDWHFKRODPLQHUJLFFHOOV $$ 7RWKHVHILYHDGGLWLRQDO

FHOOJURXSV $$ DQGWKUHHDGUHQDOLQHFRQWDLQLQJFHOOJURXSV && ZHUHDGGHG

 \HDUV ODWHU :LWK WKH GHYHORSPHQW RI QRYHO WHFKQLTXHV LW KDV EHFRPH SRVVLEOH WR

GLVWLQJXLVKEHWZHHQGLIIHUHQWFDWHFKRODPLQHV7KLVKDVOHGWRWKHGLVFRYHU\WKDWHDFKRI

GRSDPLQH QRUHSLQHSKULQH DQG HSLQHSKULQH DUH SURGXFHG E\ GLVWLQFW QHXURQV ZLWK

GHILQHGSURMHFWLRQVLQWKHEUDLQ )LJ 



Figure 3: &DWHFKRODPLQHUJLF FHOOV DQG SURMHFWLRQV LQ WKH KXPDQ EUDLQ WRS  DQG

FDWHFKRODPLQHUJLFFHOOJURXSVLQWKHPRXVHEUDLQ ERWWRP 



&HOO JURXSV $$ DOO FRQWDLQ GRSDPLQHUJLF QHXURQV DQG DUH RUJDQL]HG LQWR

WKUHH PDMRU V\VWHPV WKH PHVHQFHSKDOLF $$  GLHQFHSKDOLF $$  DQG WKH

ROIDFWRU\ $  V\VWHPV 7KH VXEVWDQWLD QLJUD SDUV FRPSDFWD 61SF $  DQG WKH

YHQWUDOWHJPHQWDODUHD 97$$ FRQWDLQWKHYDVWPDMRULW\RIGRSDPLQHUJLFQHXURQV

LQ WKH &16 DQG SOD\ FHQWUDO UROHV LQ 3DUNLQVRQ¶V GLVHDVH 3'  SDWKRORJ\ DQG UHZDUG

VLJQDOLQJUHVSHFWLYHO\ 7ULWVFK 6DEDWLQL 7KHPLGEUDLQGRSDPLQHUJLFQHXURQV

ZHUH WUDGLWLRQDOO\ VHSDUDWHG LQWR WZR PDMRU VXEW\SHV ZLWK GLVWLQFW SURMHFWLRQV WKH

QLJURVWULDWDOQHXURQVRIWKH$JURXSDQGWKH$QHXURQVSURMHFWLQJIURPWKH97$WR

OLPELFDQGFRUWLFDODUHDV0RUHUHFHQWO\WKLVKDVEHHQGHHPHGDQRYHUVLPSOLILFDWLRQ

to striatum

adrenaline noradrenaline dopamine

to spinal cord Locus coeruleus

Ventral tegmental area Substantia nigra

Medulla

A10A9A8 A11 A12 A13 A14 A15 A16

A1 A2 A5

A7 C2

C1 A6C3 A4

(19)

  

DQG PLGEUDLQ GRSDPLQH QHXURQV DUH LQVWHDG GLYLGHG LQWR D GRUVDO DQG D YHQWUDO WLHU

%MRUNOXQG 'XQQHWW 7KHGRUVDOWLHULQFOXGHV$DQGWKHGRUVDOSDUWRI$DQG

$ DQG WKH YHQWUDO WLHU LQFOXGHV WKH YHQWUDO SDUWV RI $ DQG $ 1HXURQV LQ WKH

GRUVDOWLHUH[WHQGWKHLUD[RQVWRYHQWUDOVWULDWDOFRUWLFDODQGOLPELFDUHDV %MRUNOXQG  'XQQHWW   7KHVH PHVRFRUWLFROLPELF GRSDPLQH SURMHFWLRQV GLUHFW UHVSRQVHV WR

UHZDUG DQG DUH LQYROYHG LQ GHSUHVVLYH V\PSWRPV DV ZHOO DV DIIHFWHG E\ PDQ\

SV\FKRVWLPXODQWV 1HXURQV LQ WKH YHQWUDO 61 H[WHQG WKHLU D[RQV H[FOXVLYHO\ WR WKH

VWULDWXP %MRUNOXQG  'XQQHWW   7KLV QLJURVWULDWDO SDWKZD\ LV LQVWUXPHQWDO LQ

UHJXODWLRQRIPRWRUIXQFWLRQDQGVWURQJO\DIIHFWHGLQ3'1HXURQVLQWKHYHQWUDO97$

DOVRH[FOXVLYHO\SURMHFWWRWKHVWULDWXPDQGDUHOLNHZLVHLQYROYHGLQUHJXODWLRQRIPRWRU

IXQFWLRQEXWDIIHFWHGWRDORZHUH[WHQWLQ3' %MRUNOXQG 'XQQHWW 



$OOQRUDGUHQHUJLFFHOOJURXSV $$ DUHORFDWHGLQQXFOHLZLWKLQWKHSRQVDQG

WKHPHGXOODREORQJDWD .YHWQDQVN\HWDO6P\WKLHV )RXURIWKHVHJURXSV

$$$DQG$ DUHORFDWHGZLWKLQWKHORFXVFRHUXOHXV .YHWQDQVN\HWDO

6P\WKLHV   DQG H[WHQG DVFHQGLQJ SURMHFWLRQV WR WKH IRUHEUDLQ LQFOXGLQJ WKH

K\SRWKDODPXVFHUHEUDOFRUWH[DQGOLPELFV\VWHP DQGWKHFHUHEHOOXP&HOOJURXSV$

DQG $ DUH ORFDWHG LQ WKH YHQWUDOFDXGDO SRUWLRQ RI WKH ORFXV FRHUXOHXV DQG WKH

VXEFRHUXOHXVDUHDDQGH[WHQGGHVFHQGLQJD[RQVWRWKHVSLQDOFRUG,QDFFRUGDQFHZLWK

WKHLU ZLGHVSUHDG SURMHFWLRQV QRUDGUHQHUJLF QHXURQV DUH LQYROYHG LQ D YDULHW\ RI

IXQFWLRQV LQFOXGLQJ PRWRU FRQWURO UHZDUG OHDUQLQJ PHPRU\ IHDU VWUHVV DQG PRRG

6RIXRJOX 6HZHOO 1RUDGUHQDOLQHUHOHDVHDSSHDUVWREHWKH PDLQHIIHFWRURI

VXEMHFWLYHUHZDUGDQGUHODSVHLQSV\FKRVWLPXODQWDGGLFWLRQ 6RIXRJOX 6HZHOO 

DQGHDUO\GHDWKRIQRUDGUHQHUJLFQHXURQVLQWKHORFXVFRHUXOHXVLVDOVRREVHUYHGLQ3'



7KH DGUHQHUJLF FHOO JURXSV && DUH ORFDWHG LQ WKH PHGXOOD REORQJDWD DQG

SURMHFWWRWKHSHULDTXHGXFWDOJUD\PDWWHUWKHORFXVFRHUXOHXVWKHVSLQDOFRUGDQGVWUHVV

VHQVLWLYH QXFOHL LQ WKH K\SRWKDODPXV DQG DP\JGDOD .YHWQDQVN\ HW DO  

$GUHQHUJLF QHXURQV PDLQO\ UHJXODWH VWUHVV UHVSRQVHV DQG QHXURHQGRFULQH VLJQDOLQJ

3DFDN 3DONRYLWV $GUHQHUJLFV\VWHPVDUHOHVVDIIHFWHGE\3DUNLQVRQ¶VGLVHDVH

DQGSV\FKVRVWLPXODQWVWKDQWKHGRSDPLQHUJLFDQGQRUDGUHQHUJLFV\VWHPVDQGZLOOWKXV

QRWEHGLVFXVVHGLQGHWDLOLQWKLVWKHVLV



 0HGLDWRUVRI&DWHFKRODPLQHUJLF6LJQDOLQJ

&DWHFKRODPLQHUJLF VLJQDOLQJ LV UHJXODWHG DW WKH OHYHOV RI SURGXFWLRQ H[SUHVVLRQ DQG

DFWLYLW\ RI V\QWKHVL]LQJ HQ]\PHV  UHOHDVH VLJQDO WUDQVGXFWLRQ FRXSOLQJ H[SUHVVLRQ

GHVHQVLWL]DWLRQ DQG PLFURHQYLURQPHQW RI UHFHSWRUV  DQG VLJQDO WHUPLQDWLRQ XSWDNH

WKURXJK VSHFLILF WUDQVSRUWHUV DQG DFWLYLW\ RI GHJUDGLQJ HQ]\PHV  7KH V\QWKHVL]LQJ

HQ]\PHV DUH GLVSOD\HG LQ )LJ  DQG WKH FHOO VSHFLILF H[SUHVVLRQ RI WKHVH HQ]\PHV

GHWHUPLQHV WKH LGHQWLW\ RI WKH FDWHFKRODPLQHUJLF WUDQVPLWWHU (DFK FDWHFKRODPLQH FDQ

DFWLYDWHVHYHUDOGLVWLQFWSUHV\QDSWLFDQGSRVWV\QDSWLF*3&5VDYDULHW\ZKLFKLVFUXFLDO

IRUVSDWLDODQGWHPSRUDOVLJQDOVSHFLILFLW\



7KHGRSDPLQHUHFHSWRUVDUHGLYLGHGLQWRWZRIDPLOLHVWKH'OLNHDQGWKH'OLNH

UHFHSWRUV 7KH 'OLNH UHFHSWRUV LQFOXGH UHFHSWRUV ' DQG ' ZKLFK ERWK FRXSOH WR

*ĮVROISURWHLQVDQGDFWLYDWHDGHQ\O\OF\FODVHOHDGLQJWRLQFUHDVHGLQWUDFHOOXODUF$03

OHYHOVDQGSURWHLQNLQDVH$ 3.$ DFWLYDWLRQ7KH'OLNHUHFHSWRUVLQFOXGHUHFHSWRUV

(20)



''DQG'ZKLFKFRXSOHWR*ĮLRSURWHLQVDQGLQKLELWF$03SURGXFWLRQDQG3.$

DFWLYLW\ WKURXJK LQKLELWLRQ RI DGHQ\O\O F\FODVH 'OLNH UHFHSWRUV FDQ DOVR VLJQDO

LQGHSHQGHQWO\IURP3.$WKURXJKUHOHDVHRIWKH*ȕȖVXEXQLWVRIWKH*SURWHLQ7KHVH

VXEXQLWVFDQGLIIXVHDORQJWKHSODVPDPHPEUDQHDQGGLUHFWO\DFWLYDWHLRQFKDQQHOVRU

VHFRQGPHVVHQJHUV,QFRQWUDVWWRUHFHSWRUVRIWKH'IDPLO\ZKLFKDUHSUHGRPLQDQWO\

SRVWV\QDSWLF'W\SHUHFHSWRUVDUHH[SUHVVHGERWKSUHDQGSRVWV\QDSWLFDOO\ %HDXOLHX

*DLQHWGLQRY)HXHUVWHLQ 



1RUDGUHQDOLQH DQG DGUHQDOLQH ERWK DFWLYDWH DGUHQHUJLF UHFHSWRUV $GUHQHUJLF

UHFHSWRUVDUHGLYLGHGLQWRWKUHHIDPLOLHVĮĮDQGȕ %\OXQGHWDO 5HFHSWRUVRI

WKH Į IDPLO\ DUH FRXSOHG WR *ĮT SURWHLQV ZKLFK DFWLYDWH SKRSKROLSDVH & DQG

SKRVSKRLQRVLWRO VHFRQG PHVVHQJHUV 6RIXRJOX  6HZHOO   7KHVH UHFHSWRUV DUH

PDLQO\ H[FLWDWRU\ DQG ORFDWHG SRVWV\QDSWLFDOO\ LQ ERWK QHXURQV DQG JOLDO FHOOV

5HFHSWRUVRIWKHĮIDPLO\DUHFRXSOHGWR*DLRDQGLQKLELWF$03IRUPDWLRQWKURXJKWKH

LQKLELWLRQRIDGHQ\ODWHF\FODVH 6RIXRJOX 6HZHOO 7KHVHUHFHSWRUVDUHORFDWHG

ERWKSUHDQGSRVWV\QDSWLFDOO\LQWKH&16DQGWKXVDFWERWKDVVLJQDOWUDQVGXFHUVDQGDV

DXWRUHFHSWRUV PRGXODWLQJ QRUDGUHQHUJLF IXQFWLRQ %\OXQG HW DO   7KH UROH RI ȕ

DGUHQHUJLFUHFHSWRUVLQWKH&16LVOHVVFOHDUWKDQIRUĮDGUHQHUJLFUHFHSWRUV0HPEHUV

RI WKH ȕ IDPLO\ FRXSOH WR *DV SURWHLQV DQG WKXV VWLPXODWH F$03 IRUPDWLRQ WKURXJK

DFWLYDWLRQRIDGHQ\ODWHF\FODVH



7HUPLQDWLRQ RI FDWHFKRODPLQH VLJQDOLQJ RFFXUV WKURXJK UDSLG UHXSWDNH LQWR

SUHV\QDSWLF WHUPLQDOV YLD VSHFLILF WUDQVSRUWHUV 'RSDPLQH LV WDNHQ XS YLD GRSDPLQH

WUDQVSRUWHUV '$7  .XKDUHWDO DQGDGUHQDOLQHDQGQRUDGUHQDOLQHDUHWDNHQXS

E\ QRUHSLQHSKULQH WUDQVSRUWHUV 1(7  '$7 DQG 1(7 FDQ KRZHYHU WUDQVSRUW

FDWHFKRODPLQHV LQ ERWK GLUHFWLRQV DQG RQH PDMRU FDXVH RI WKH SV\FKRVWLPXODQW

SURSHUWLHV RI DPSKHWDPLQHV LV WKHLU UHYHUVDO RI '$7 DQG 1(7 WUDQVSRUW OHDGLQJ WR

LQFUHDVHG H[WUDFHOOXODU GRSDPLQH DQG QRUDGUHQDOLQH OHYHOV .XKDU HW DO  

&DWHFKRODPLQHVFDQDOVREHLQDFWLYDWHGWKURXJKGHJUDGDWLRQE\PRQRDPLQHR[LGDVH$

0$2$  RU DW KLJK H[WUDFHOOXODU FRQFHQWUDWLRQV E\ FDWHFKRORPHWK\O WUDQVIHUDVH

&207 



 3$5.,1621¶6',6($6(

3DUNLQVRQ¶VGLVHDVH 3' LVWKHVHFRQGPRVWIUHTXHQWQHXURGHJHQHUDWLYHGLVRUGHUDIWHU

$O]KHLPHU¶VGLVHDVHDIIHFWLQJDERXWRIWKHSRSXODWLRQRYHU\HDUVRIDJH /HHV

HWDO $SDWKRORJLFDOKDOOPDUNDQGFDXVHRIPRVWV\PSWRPVLVWKHSURJUHVVLYH

GHDWK RI FDWHFKRODPLQHUJLF QHXURQV 7KLV PDLQO\ LQYROYHV QLJURVWULDWDO GRSDPLQHUJLF

QHXURQVEXWGHJHQHUDWLRQRIROIDFWRU\QHXURQVDQGQRUDGUHQHUJLFQHXURQVLQWKHORFXV

FRHUXOHXVLVDOVRREVHUYHGDOUHDG\DWDQHDUO\VWDJHRIGLVHDVH /HHVHWDO 3'LV

PDLQO\ UHFRJQL]HG IURP LWV FKDUDFWHULVWLF PRWRU LPSDLUPHQWV VXFK DV SRVWXUDO

LQVWDELOLW\ VORZQHVV RU DEVHQFH RI YROXQWDU\ PRYHPHQW WUHPRU DW UHVW ULJLGLW\ DQG

IUHH]LQJ 'DXHU  3U]HGERUVNL   +RZHYHU PRVW SDWLHQWV DOVR VXIIHU IURP

DXWRQRPLF G\VIXQFWLRQV DQG QHXURSV\FKLDWULF V\PSWRPV ZKLFK RIWHQ SUHFHGH PRWRU

V\PSWRPV 'DXHU  3U]HGERUVNL   7KHVH V\PSWRPV PD\ LQFOXGH ODFN RI

LQLWLDWLYHVORZHGFRJQLWLYHSURFHVVHVVOHHSGLVWXUEDQFHVKDOOXFLQDWLRQVDQGLQRI

DOOSDWLHQWVGHSUHVVLRQ 'DXHU 3U]HGERUVNL/HHVHWDO 



(21)

  

7KHPRVWFRPPRQDJHQWWRWUHDW3'V\PSWRPVLVWKHGRSDPLQHSUHFXUVRU/GRSD

/GRSD LPSURYHV PRWRU V\PSWRPV LQ PRVW SDWLHQWV EXW FKURQLF WUHDWPHQW LV RIWHQ

DVVRFLDWHG ZLWK LQYROXQWDU\ PRYHPHQWV FDOOHG G\VNLQHVLDV /HHV HW DO   1RQ

HUJROLQHGRSDPLQHDJRQLVWV VXFKDVSUDPLSH[ROHURSLQLUROHURWLJRWLQHDQGSLULEHGLO  DUH FRPPRQ WUHDWPHQWV LQ HDUO\ 3' DQG LQGXFH OHVV G\VNLQHVLDV 7KHVH FRPSRXQGV

KRZHYHU KDYH ZHDNHU DQWL3DUNLQVRQLDQ HIIHFWV DQG FDXVH JDVWURLQWHVWLQDO DQG

SV\FKLDWULFVLGHHIIHFWV7KHPRQRDPLQHR[LGDVH%LQKLELWRUVVHOHJLOLQHDQGUDVDJLOLQH

DUHDOVRLQFXUUHQWFOLQLFDOXVHDQGLQVRPHFDVHVVXUJLFDOLPSODQWDWLRQRIDQHOHFWURGH

WR VSHFLILFDOO\ VWLPXODWH WKH VXEWKDODPLF QXFOHXV LV XVHG WR LPSURYH 3' V\PSWRPV

%HUJPDQHWDO*XULGLHWDO :KLOHWKHVWUDWHJLHVWRWUHDW3'V\PSWRPVDUH

VWHDGLO\ HYROYLQJ QRQH RI WKH FXUUHQW WUHDWPHQWV KDYH SURYHQ GLVHDVHPRGLI\LQJ

HIIHFWV7KHUHLVWKXVDKLJKQHHGIRUQRYHOGUXJVWKDWKDOWRUGHOD\WKHSURJUHVVLRQRI

3' 7R WKLV HQG D EHWWHU XQGHUVWDQGLQJ RI WKH VHTXHQFH DQG LQWHUGHSHQGHQFH RI

SDWKRJHQLFHYHQWVZLOOEHQHFHVVDU\LQFOXGLQJWKHSRWHQWLDOUROHRI3DUNLQDQG*35

LQGLVHDVHLQLWLDWLRQDQGSURJUHVVLRQ



 3DWKRJHQHVLV

:KLOHPXFKLVODFNLQJLQWKHXQGHUVWDQGLQJRIFDXVDWLYHPHFKDQLVPVLQ3'DQXPEHU

RISDWKRORJLFSKHQRPHQDWKDWFRXOGFRQWULEXWHWRGLVHDVHSURJUHVVLRQDQGRULQLWLDWLRQ

KDYH EHHQ REVHUYHG LQ ERWK 3' FDVHV DQG H[SHULPHQWDO PRGHOV 7KHVH SKHQRPHQD

LQFOXGH R[LGDWLYH VWUHVV PLWRFKRQGULDO G\VIXQFWLRQ SURWHLQ PLVIROGLQJ DQG

DJJUHJDWLRQSURWHDVRPDODQGO\VRVRPDOG\VIXQFWLRQDQGLQIODPPDWLRQ0RVW3'FDVHV

DUHVSRUDGLFLHZLWKQRDSSDUHQWJHQHWLFOLQNDJHEXWLQDERXWRIDOOFDVHVWKH

GLVHDVHLVFDXVHGE\LQKHULWHGJHQHWLFPXWDWLRQV7KHIXQFWLRQRIWKHJHQHVPXWDWHGLQ

IDPLOLDO 3' HQYLURQPHQWDO ULVN IDFWRUV VXFK DV SHVWLFLGH H[SRVXUH WUDXPDWLF KHDG

LQMXU\DQGDJHDQGDOWHUDWLRQVLQSRVWPRUWHPEUDLQVIURP3'SDWLHQWVKDYHGLUHFWHG

LQYHVWLJDWLRQVRISRWHQWLDOSDWKRJHQLFPHFKDQLVPVDQGOHGWRLPSURYHGNQRZOHGJHRQ

SDWKRJHQLFSURFHVVHV



1.3.1.1 Oxidative stress

'RSDPLQHUJLFQHXURQVRIWKHVXEVWDQWLDQLJUDSDUVFRPSDFWD 61SF UHSUHVHQWWKHYDVW

PDMRULW\RIQHXURQDOGHDWKLQ3'7KHVHQHXURQVFRQWDLQKLJKOHYHOVRIQHXURPHODQLQ

ZKLFKFRQVLVWVRIUHGXFHGGRSDPLQHGRSDPLQHPHWDEROLWHVOLSLGVDQGSURWHLQVDQGLV

WKRXJKW WR VHUYH DV DQ LURQ VWRUDJH FRPSRQHQW 'RXEOH HW DO   'RSDPLQHUJLF

QHXURQVRIWKH61SFPD\EHSDUWLFXODUO\VHQVLWLYHWRR[LGDWLYHVWUHVVGXHWRWKHLUKLJK

QHXURPHODQLQ FRQWHQW DQG VLQFH WKH PHWDEROLVP DQG DXWRR[LGDWLRQ RI GRSDPLQH

JHQHUDWHV UHDFWLYH R[\JHQ VSHFLHV 526  'RXEOH HW DO  *UDKDP HW DO  

526 DUH KLJKO\ WR[LF WR FHOOV SDUWLFXODUO\ QHXURQV DQG PDUNHUV RI SURWHLQ DQG OLSLG

R[LGDWLRQ KDYH EHHQ IRXQG LQ WKH VXEVWDQWLD QLJUD RI 3' SDWLHQWV $QGHUVHQ  

0RUHRYHU DFWLYLW\ RI WKH DQWLR[LGDQW HQ]\PH JOXWDWKLRQH6WUDQVIHUDVH *67  LV

UHGXFHGLQWKH61SFRI3'SDWLHQWVDQG*67DFWLYLW\LVORZHULQWKHPRUHYXOQHUDEOH

GRSDPLQHQHXURQVLQWKHYHQWUDOWLHURIWKH61SFFRPSDUHGWRWKRVHLQWKHGRUVDOWLHU

$QGHUVHQ'RXEOHHWDO 7KHLGHDWKDWR[LGDWLYHVWUHVVFDXVHV3'JDLQHG

IXUWKHUVXSSRUWDIWHUWKHGLVFRYHU\WKDW0373DWR[LQWKDWFDXVHV3'LQKLELWVFRPSOH[

, RI WKH PLWRFKRQGULDO HOHFWURQ WUDQVSRUW FKDLQ 1LFNODV HW DO   6XEVHTXHQWO\

GHILFLHQFLHV LQ FRPSOH[ , IXQFWLRQ ZHUH DOVR IRXQG LQ 3' *UHHQDP\UH HW DO  

7KH PLWRFKRQGULD DUH WKH PDLQ VLWHV RI 526 JHQHUDWLRQ LQ WKH FHOO DQG FRPSOH[ ,

(22)



LQKLELWLRQFDQFDXVHHQHUJ\ IDLOXUHDQGH[FHVVLYHJHQHUDWLRQ RI 526,QFUHDVHG526

FRXOGLQWXUQIXUWKHULQKLELWWKHPLWRFKRQGULDOHOHFWURQWUDQVSRUWFKDLQ &RKHQ  DQGGLVUXSWYHVLFXODUVWRUDJHRIGRSDPLQHLQFUHDVLQJWKHF\WRVROLF526FRQFHQWUDWLRQV

DQG DOORZLQJ LQFUHDVHG SURGXFWLRQ RI WR[LF GRSDPLQH PHWDEROLWHV 'DXHU  3U]HGERUVNL   526 FDQ DOVR GLVUXSW SURWHDVRPH IXQFWLRQ DQG LQGXFH SURWHLQ

PLVIROGLQJJOLDOFHOODFWLYDWLRQDQGSURJUDPPHGFHOOGHDWKHYHQWVZKLFKFDQDOOLQWXUQ

OHDG WR LQFUHDVHG 526 SURGXFWLRQ $QGHUVHQ   7KLV LQWHUGHSHQGHQFH EHWZHHQ

R[LGDWLYHVWUHVVDQGRWKHUSDWKRJHQLFPHFKDQLVPVREVHUYHGLQ3'OLNHO\FRQWULEXWHVWR

WKH SDWKRJHQLF ORRS EXW DOVR FRPSOLFDWHV WKH GLVWLQFWLRQ EHWZHHQ FDXVDWLYH

PHFKDQLVPV DQG VHFRQGDU\ HIIHFWV ,W LV KHQFH XQFOHDU ZKHWKHU R[LGDWLYH VWUHVV FDQ

FDXVH WKH GLVHDVH RU ZKHWKHU LW LV D UHVXOW RI FHOO GHDWK WKDW PD\ H[DFHUEDWH

QHXURGHJHQHUDWLRQ



1.3.1.2 Mitochondrial dysfunction

0LWRFKRQGULDDUHFRPPRQO\FDOOHGWKH³SRZHUSODQWVRIWKHFHOO´GXHWRWKHLUHQHUJ\

SURGXFWLRQ WKURXJK R[LGDWLYH SKRVSKRU\ODWLRQ DQG KDUERULQJ RI WKH HOHFWURQ WUDQVSRUW

FKDLQ ZKLFK JHQHUDWHV WKH FHOOXODU HQHUJ\ VRXUFH $73 7KH\ DOVR IXQFWLRQ LQ

PDLQWHQDQFHRIFHOOXODU&DKRPHRVWDVLVDQGLQOLSLGDPLQRDFLGFDUERK\GUDWHDQG

VWHURLGPHWDEROLVP 0DUWLQH] *UHHQDP\UH ,QDGGLWLRQWRLPSDLUHGFRPSOH[,

DFWLYLW\DQLQFUHDVHGQXPEHURIGHOHWLRQVWR PLWRFKRQGULDO'1$ PW'1$ KDVEHHQ

REVHUYHG SRVWPRUWHP LQ WKH 61SF RI 3' SDWLHQWV 0DUWLQH]  *UHHQDP\UH 

6FKRQ  3U]HGERUVNL   6XFK GHOHWLRQV DUH OLNHO\ WR OHDG WR D ODUJHU IUDFWLRQ RI

IDXOW\ PLWRFKRQGULD WKDW PD\ GLVUXSW FHOOXODU KRPHRVWDVLV ERWK WKURXJK ORVV RI WKHLU

QRUPDO IXQFWLRQ DQG WKURXJK H[FHVVLYH 526 SURGXFWLRQ 'DPDJHG PLWRFKRQGULD DUH

HOLPLQDWHG E\ WKH FHOO WKURXJK PLWRFKRQGULDO DXWRSKDJ\ PLWRSKDJ\  RU LQFRUSRUDWHG

LQWRIXQFWLRQDOPLWRFKRQGULDWKURXJKPLWRFKRQGULDOIXVLRQWRDWWHQXDWHWKHLUGHOHWHULRXV

HIIHFWV 6FKRQ 3U]HGERUVNL $QXPEHURIUHFHQWVWXGLHVVKRZWKDW3,1.DQG

3DUNLQ WZR SURWHLQV ZKRVH PXWDWHG IRUPV FDXVH IDPLOLDO 3' LQWHUDFW WR SURPRWH

PLWRSKDJ\ *HLVOHUHWDO-LQHWDO1DUHQGUDHWDO9LYHV%DX]D  3U]HGERUVNL9LYHV%DX]DHWDO '-DQRWKHUSURWHLQWKDWLVPXWDWHGLQ

IDPLOLDO3'LVDOVRLPSOLFDWHGLQPLWRFKRQGULDOTXDOLW\FRQWURODVLWLQWHUDFWVZLWKERWK

3DUNLQ DQG 3,1. DQG UHJXODWHV PLWRFKRQGULDO ILVVLRQIXVLRQ ,UUFKHU HW DO 

0RRUHHWDO )LQDOO\LQFUHDVHGIUDJPHQWDWLRQRIPLWRFKRQGULDLVUHSRUWHGDIWHU

RYHUH[SUHVVLRQRIĮV\QXFOHLQWKHPDLQFRPSRQHQWRI/HZ\ERGLHVDQGDSURWHLQIRU

ZKLFKJHQHPXOWLSOLFDWLRQVDUHIRXQGLQVRPH3'FDVHV .DPSHWDO1DNDPXUD

HW DO   7KHVH JHQHWLF OLQNV FRUUHODWH ZHOO ZLWK WKH IDFW WKDW VHYHUDO WR[LQV WKDW

LQGXFH 3DUNLQVRQLVP LQKLELW FRPSOH[ , 0373 DQG URWHQRQH  DQGRU LQGXFH

PLWRFKRQGULDO ILVVLRQ 2+'$ DQG URWHQRQH  0DUWLQH]  *UHHQDP\UH  

FROOHFWLYHO\VXSSRUWLQJDUROHRIPLWRFKRQGULDLQ3'SDWKRJHQHVLV



1.3.1.3 Protein misfolding and aggregation

3'SDWKRORJ\LVFKDUDFWHUL]HGE\ODUJHLQWUDFHOOXODUGHSRVLWLRQVRIDJJUHJDWHGSURWHLQV

/HZ\ERGLHVRQHRIWKHSDWKRORJLFDOKDOOPDUNVRI3'ODUJHO\FRQVLVWRIXQIROGHGDQG

DJJUHJDWHG SURWHLQV DVVRFLDWHG PROHFXODU FKDSHURQHV XELTXLWLQ DQG SURWHDVRPDO

VXEXQLWV 3URWHLQ PLVIROGLQJ DQG DJJUHJDWLRQ FDQ EH WULJJHUHG E\ R[LGDWLYH VWUHVV

PLWRFKRQGULDO G\VIXQFWLRQ JHQHWLF PXWDWLRQV RU RYHUORDG RI WKH FHOOXODU SURWHLQ

SURGXFWLRQPDFKLQHU\2QFHPLVIROGHGSURWHLQVFDQHLWKHUEHUHIROGHGE\DVVLVWDQFHRI

(23)

  

PROHFXODU FKDSHURQHV OLQNHG WR XELTXLWLQ ZKLFK WDUJHWV WKHP WR SURWHDVRPHV IRU

GHJUDGDWLRQ RU GHJUDGHG E\ DXWRSKDJ\ 5RVV  3RLULHU   3URWHLQ IROGLQJ DQG

SURFHVVLQJPDLQO\RFFXUVLQWKHHQGRSODVPLFUHWLFXOXP (5 ,IXQIROGHGSURWHLQVVWDUW

WRDFFXPXODWHLQWKH(5WKHXQIROGHGSURWHLQUHVSRQVH 835RU(5VWUHVVUHVSRQVH LV

DFWLYDWHG 7KLV LQFOXGHV GRZQ UHJXODWLRQ RI SURWHLQ WUDQVODWLRQ DFWLYDWLRQ RI (5

FKDSHURQHV DQG DFWLYDWLRQ RI (5DVVRFLDWHG GHJUDGDWLRQ (5$'  LQFOXGLQJ

SURWHDVRPDOGHJUDGDWLRQ :DQJ 7DNDKDVKL  (5VWUHVVWKXVKHOSVWKHFHOOWR

FRSH ZLWK WHPSRUDU\ VWUHVVRUV WKDW LQGXFH H[FHVVLYH SURWHLQ PLVIROGLQJ +RZHYHU

XQGHUFRQGLWLRQVRIVHYHUHRUSURORQJHG(5VWUHVVDSRSWRWLFVLJQDOVDUHDFWLYDWHGDQG

WKH(5VWUHVVOHDGVWRFHOOGHDWK



,Q 3' PDUNHUV RI (5 VWUHVV DUH XS UHJXODWHG 0RUHRYHU WKH WR[LQV 2+'$

0373DQGURWHQRQHZKLFKDOOFDQFDXVH3DUNLQVRQLVPLQGXFHGUDPDWLFXSUHJXODWLRQ

RI (5 VWUHVV PDUNHUV +ROW]  20DOOH\  5\X HW DO  <DPDPXUR HW DO

  6HYHUDO PXWDWLRQV FDXVLQJ IDPLOLDO 3' DOVR LQFUHDVH F\WRSODVPLF SURWHLQ

DFFXPXODWLRQ DQG DJJUHJDWLRQ 7ULSOLFDWLRQ RI WKH ĮV\QXFOHLQ JHQH RU PXWDWLRQV

OHDGLQJWRLQFUHDVHGDJJUHJDWLRQSURSHQVLW\RIĮV\QXFOHLQFDXVHDXWRVRPDOGRPLQDQW

3' DQG LQGXFH XSUHJXODWLRQ RI (5 VWUHVV PDUNHUV $FFRUGLQJO\ H[SUHVVLRQ RI WKH

PROHFXODUFKDSHURQHKHDWVKRFN SURWHLQ +VS LQDrosophilaRYHUH[SUHVVLQJĮ

V\QXFOHLQSUHYHQWHGĮV\QXFOHLQLQGXFHGGRSDPLQHUJLFFHOOORVV)XUWKHUWKHJHQHWLF

OLQNDJH EHWZHHQ 3DUNLQ PXWDWLRQV DQG 3' VXSSRUW D UROH RI (5 VWUHVV DQG SURWHLQ

DJJUHJDWHVLQ3'SDWKRJHQHVLV3DUNLQLVDQ(XELTXLWLQOLJDVHDQGLWVPDLQIXQFWLRQLV

WR PDUN LWV PLVIROGHG SURWHLQ VXEVWUDWHV IRU SURWHDVRPDO GHJUDGDWLRQ 6HYHUDO 3DUNLQ

VXEVWUDWHV DUH DJJUHJDWLRQSURQH SURWHLQV WKDW DFFXPXODWH LQ /HZ\ ERGLHV :DQJ  7DNDKDVKL DQGRYHUH[SUHVVLRQRI3DUNLQSURWHFWVFHOOVDJDLQVWXQIROGHGSURWHLQ

LQGXFHG FHOO GHDWK ,PDL HW DO   /RVV RI IXQFWLRQ PXWDWLRQV LQ WKH 3DUNLQ JHQH

FDXVH DXWRVRPDO UHFHVVLYH MXYHQLOH 3' $5-3  7KHVH PXWDWLRQV UHGXFH WKH FHOO¶V

DELOLW\WRFRSHZLWKXQIROGHGSURWHLQVWUHVVDQGSURPRWHWKHDFFXPXODWLRQRIDJJUHJDWHG

3DUNLQVXEVWUDWHVLQWKH(5



2QHRIWKHPRVWZHOOVWXGLHGVXEVWUDWHVRI3DUNLQ*35LVIRXQGWRDFFXPXODWH

LQ WKH 61SF RI SDWLHQWV ZLWK $5-3 DQG LWV RYHUH[SUHVVLRQ LQ 3DUNLQ GHILFLHQW PLFH

FDXVHVDSURJUHVVLYH3DUNLQVRQLDQSKHQRW\SH ,PDLHWDO:DQJHWDOE 7KH

QHXURQDO H[SUHVVLRQ RI *35 LV OLPLWHG WR SRSXODWLRQV LQ WKH KLSSRFDPSXV DQG

GRSDPLQHUJLF QHXURQV LQ WKH 61SF 7KLV GLVWULEXWLRQ KDV EHHQ VXJJHVWHG WR SDUWLDOO\

H[SODLQ WKH VHOHFWLYH GHDWK RI GRSDPLQHUJLF QHXURQV LQ WKH 61SF LQ 3' :DQJ  7DNDKDVKL   7KH UROH RI *35 LQ FDWHFKRODPLQHUJLF FHOO VXUYLYDO LV WKH PDLQ

IRFXVRIWKLVWKHVLVDQGLWVLPSOLFDWLRQLQ3'LVGHVFULEHGLQPRUHGHWDLOEHORZ



1.3.1.4 Proteasomal and lysosomal dysfunction

3URWHDVRPDODQGO\VRVRPDOIXQFWLRQDUHLQWLPDWHO\FRQQHFWHGWRSURWHLQDJJUHJDWLRQDV

SURWHDVRPDOGHJUDGDWLRQDQGDXWRSKDJ\DUHWKHPDLQSDWKZD\VWKURXJKZKLFKWKHFHOO

FOHDUV WR[LF SURWHLQ DJJUHJDWHV 5HGXFHG SURWHDVRPH DFWLYLW\ KDV EHHQ IRXQG LQ WKH

VXEVWDQWLD QLJUD EXW QRW LQ RWKHU EUDLQ UHJLRQV RI 3' SDWLHQWV FRPSDUHG WR DJH

PDWFKHG FRQWUROV (EUDKLPL)DNKDUL HW DO   3'LQGXFLQJ WR[LQV LQFOXGLQJ

URWHQRQHDQG0373UHGXFHSURWHDVRPDODFWLYLW\DQGVHYHUDOPXWDWLRQVLQIDPLOLDO3'

DUHUHODWHGWRLPSDLUHGSURWHDVRPDOGHJUDGDWLRQ7KHVHLQFOXGHPXWDWLRQVLQ/55.

(24)



3DUNLQWKHXELTXLWLQK\GURODVH8&+/DQGĮV\QXFOHLQ (EUDKLPL)DNKDULHWDO

5RVV  3RLULHU   $JJUHJDWLRQ SURQH ĮV\QXFOHLQ PXWDQWV LQKLELW SURWHDVRPH

IXQFWLRQOHDGLQJWRLQFUHDVHGDSRSWRVLV 6WHIDQLVHWDO7DQDNDHWDO DQG

V\VWHPLF WUHDWPHQW ZLWK SURWHDVRPH LQKLELWRUV FDQ FDXVH 3DUNLQVRQLVP LQ URGHQWV

(EUDKLPL)DNKDULHWDO 0XWDQWĮV\QXFOHLQDOVRLQKLELWVDXWRSKDJ\ &XHUYRHW

DO   DQG ĮV\QXFOHLQ ROLJRPHUV SDUWLFLSDWH LQ D SDWKRJHQLF F\FOH ZKHUH WKH\

LQKLELWQRUPDOO\VRVRPDOIXQFWLRQZKLFKLQWXUQSURPRWHVIXUWKHUDFFXPXODWLRQRIĮ

V\QXFOHLQROLJRPHUV 0D]]XOOLHWDO $QLQFUHDVHRIDXWRSKDJRVRPHVKDVEHHQ

REVHUYHG LQ WKH 61 RI 3' SDWLHQWV LQGLFDWLQJ HLWKHU RYHUSURGXFWLRQ RU LPSDLUHG

WXUQRYHURIDXWRSKDJRVRPHV $QJODGHHWDO 7KHUHLVDOVRHYLGHQFHIRUUHGXFHG

O\VRVRPDOIXQFWLRQDQGUHGXFHGDXWRSKDJLFIOX[LQ/HZ\ERG\SDWKRORJLHVLQFOXGLQJ

3' (EUDKLPL)DNKDULHWDO )LQDOO\FHOOGHDWKLQ0373WUHDWHGPLFHLVSUHFHGHG

E\ SHUPHDELOL]DWLRQ RI O\VRVRPDO PHPEUDQHV DV D UHVXOW RI PLWRFKRQGULDLQGXFHG

R[LGDWLYH VWUHVV 'HKD\ HW DO   $XWRSKDJ\ LV KRZHYHU D VWURQJO\ UHJXODWHG

SURFHVV DQG HYHQ WKRXJK QRUPDO DXWRSKDJ\ LV D SURWHFWLYH PHFKDQLVP H[FHVVLYH

DXWRSKDJ\FDQOHDGWRFHOOGHDWK (EUDKLPL)DNKDULHWDO ,QFUHDVHGDXWRSKDJ\

FDQDOVREHDVLJQRIGHFUHDVHGSURWHDVRPHIXQFWLRQDOLW\SRVVLEO\DVDUHVXOWRIFHOOXODU

VWUHVVDQGYLFHYHUVD7KHLQWHUSUHWDWLRQRIWKHHIIHFWVRQDXWRSKDJ\REVHUYHGLQ3'

EUDLQV DQG PRGHOV LV WKXV QRW HQWLUHO\ FOHDU DQG WKH XWLOLW\ RI JOREDO LQFUHDVHV LQ

DXWRSKDJ\IRUQHXURSURWHFWLRQLVTXHVWLRQDEOH



1.3.1.5 Inflammation

7KH FRQFHSW RI QHXURLQIODPPDWLRQ DV D SRWHQWLDO SDWKRJHQLF SDWKZD\ LQ 3' LV

UHODWLYHO\QHZ7KHHQWU\RILPPXQHFHOOVLQWRWKH&16LVEORFNHGE\WKHEORRGEUDLQ

EDUULHU DQG LPPXQH VXUYHLOODQFH LQ WKH &16 LV LQVWHDG KDQGOHG E\ DVWURF\WHV DQG

PLFURJOLD $VWURF\WHV FDQ SURWHFW QHXURQV IURP HQHUJ\ IDLOXUH DQG R[LGDWLYH VWUHVV

%ODFNEXUQ HW DO   7KH\ DUH DOVR UHFUXLWHG WR VLWHV RI LQMXU\ ZKHUH WKH\ UHGXFH

LQIODPPDWRU\LQILOWUDWLRQUHSDLUWKHEORRGEUDLQEDUULHUDQGFOHDUGHEULV %ODFNEXUQHW

DO  3KDQL HW DO   0LFURJOLD LQ WKHLU UHVWLQJ VWDWH DUH LQYROYHG LQ

PDLQWHQDQFH RI KRPHRVWDVLV RI WKH QHXUDO HQYLURQPHQW 8QGHU FRQGLWLRQV RI VWUHVV

PLFURJOLDEHFRPHDFWLYDWHGDQGVHFUHWHDYDULHW\RIQHXURWURSKLFIDFWRUVDQGF\WRNLQHV

.HWWHQPDQQHWDO3KDQLHWDO $FWLYDWHGPLFURJOLDDOVRFOHDUWKHVLWHIURP

SDWKRJHQVGHEULVDQGGDPDJHGFHOOVDQGV\QDSVHVWKURXJKSKDJRF\WRVLV .HWWHQPDQQ

HWDO ,QIODPPDWRU\UHVSRQVHVLQYROYLQJDVWURF\WHVDQGPLFURJOLDKDYHWKXVORQJ

EHHQ FRQVLGHUHG SXUHO\ EHQHILFLDO WR QHXURQDO VXUYLYDO ,W LV KRZHYHU EHFRPLQJ

LQFUHDVLQJO\FOHDUWKDWXQUHJXODWHGDVWURF\WHDQGPLFURJOLDODFWLYDWLRQFDQEHKDUPIXOWR

QHXURQV8QUHJXODWHGPLFURJOLDODFWLYDWLRQOHDGVWRH[FHVVLYHUHOHDVHRI526UHDFWLYH

QLWURJHQ VSHFLHV 516  DQG SURLQIODPPDWRU\ SURVWDJODQGLQV DQG F\WRNLQHV 3KDQL HW

DO   ,QFUHDVHG OHYHOV RI WKH SURVWDJODQGLQV\QWKHVL]LQJ HQ]\PH &R[ DQG WKH

SURLQIODPPDWRU\ F\WRNLQH ,/ȕ KDYH EHHQ IRXQG LQ WKH 61SF RI 3' SDWLHQWV DQG

LQKLELWRQRI&R[FDQSURWHFWPLFHIURP0373DQG2+'$LQGXFHGWR[LFLW\ 3KDQL

HWDO 5HVXOWVIURPVWXGLHVLQDQLPDOPRGHOVDOVRVXJJHVWWKDW0373URWHQRQHRU

H[WUDFHOOXODU ĮV\QXFOHLQ WULJJHU PLFURJOLDO DFWLYDWLRQ LQ WKH 61SF SULRU WR

GRSDPLQHUJLF FHOO GHDWK +DOOLGD\  6WHYHQV   7KH H[DFW PHFKDQLVPV RI JOLDO

DFWLYDWLRQ DQG LWV UROH LQ QHXURWR[LFLW\ RU QHXURSURWHFWLRQ DW GLIIHUHQW VWDJHV RI 3'

KRZHYHUVWLOOUHTXLUHVLJQLILFDQWHOXFLGDWLRQ



References

Outline

Related documents

EHLQJ WRR WRSGRZQ DQG LQIOH[LEOH &gt;@ WDNLQJ DZD\ WKH EHQHILWV RI DXWRQRP\ WR

DQG DVVXPSWLRQV WKDW DIIHFW WKH UHSRUWHG DPRXQWV RI DVVHWV OLDELOLWLHV DQG H[SHQGLWXUHV 7KHVH HVWLPDWHV DQG. DVVXPSWLRQV DUH EDVHG RQ PDQDJHPHQW¶V

Lq ghyhorslqj wkh vlpxodwlrq prgho/rxu dpelwlrq kdv ehhq wr nhhs wkh prgho vlpsoh dqg wr plqlpl}h wkh qxpehu ri yduldeohv wr eh prghoohg1 Frq0 vhtxhqwo|/wkh prgho jlyhv d

Wkh sxusrvh ri wklv uhsruw lv wr ghvfuleh wkh prgho wkdw wkh Vzhglvk Qdwlrqdo Ghew R!fh kdv ghyhorshg iru vwxg|lqj wkh hhfwv ri wkh fkrlfh ri gxudwlrq dqg fxuuhqf| frpsrvlwlrq lq

%ROLYLDQ HOLWHV DQG VWLOO OHIW WKH OHVV SULYLOHJHG SRSXODWLRQ ZLWK IRRG RI GRXEWIXO. TXDOLW\ $JDLQ , VKRZ WKDW WKH V\PEROLF DQG WKH PDWHULDO FRPH

VRIWZDUH DQG WHFKQLTXHV WKH LQIRUPDWLRQ VKRXOG EH SUHVHQWHG WR WKH SXEOLF LQ DQ HDV\WRXVH DQG HDV\WR XQGHUVWDQG ZD\ LQ RUGHU WR UHDFK WKH ODUJHVW SRVVLEOH SHUFHQWDJH RI WKH WDUJHW

'HWHUPLQDWLRQ RI WKH SDUWLDO FRHIILFLHQW ηγ P  ZLWK WKH WDEOH PHWKRG DQG WKH SUREDELOLVWLFPHWKRGJLYHVVOLJKWO\GLIIHUHQWUHVXOWVIRUWKHVHYHQEULGJHVEHWZHHQ /XOHn

FRQ DQG IURP WKH 53 SODVPLG WR SUHSDUH WKH FRQVWUXFWLRQ RI D VL]HUHGXFHG PRELOL]DEOH YHUVLRQ RI S304$. )XUWKHUPRUH IRXU %LR%ULFN DQWLELRWLF UHVLVWDQFH FDVVHWWHV ZHUH H[WUDFWHG