)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
*35W*)3JUHHQRQWKHVXUIDFHRIWKHFHOOERG\DQGSURFHVVHVDQGLQGHQGULWLFVSLQHV
$OOSUHYLRXVO\SXEOLVKHGSDSHUVZHUHUHSURGXFHGZLWKSHUPLVVLRQIURPWKHSXEOLVKHU
3XEOLVKHGE\.DUROLQVND,QVWLWXWHW3ULQWHGE\cWWD7U\FNHUL$%
(EED*UHJRUVVRQ/XQGLXV ,6%1
$%675$&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
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
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\WDQ6HILJXU$
'lUHPRW YHUNDGH UHFHSWRUHUQD LQWH NOXPSD LKRS VLJ L QnJRQ K|JUH JUDG L GH KlU
FHOOHUQD7LOOPLQI|UYnQLQJXSSWlFNWHMDJRFNVnDWWQlUMDJEHKDQGODGHFHOOHUQDVnDWWGH
EOHYOLNDGRSDPLQQHUYFHOOHUI|UIO\WWDGHVVW|UUHGHOHQDYUHFHSWRUHUQDIUnQFHOOHQVLQVLGD
WLOOFHOO\WDQ6HILJXU%'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
$ %
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|NDGHLQQHLFHOOHQ6HILJXU-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
LQIlUJQLQJHQRFKGHQJU|QDIOXRUHVFHQVHQIUnQ*35EHIDQQVLJSnVDPPDVWlOOHQSn
FHOO\WDQRFKDWWSnGHVWlOOHQGlUGHWYDUH[WUDP\FNHW*0YDUGHWRFNVnH[WUDP\FNHW
*356HILJXU$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$$5 VRP UHJOHUDU GRSDPLQQHUYFHOOHUV
VLJQDOHULQJ 6LJQDOHULQJ PHOODQ QHUYFHOOHU VNHU L Vn NDOODGH V\QDSVHU GYV
PHOODQUXPPHWPHOODQDYVlQGDUFHOOHQVXWVNRWWRFKPRWWDJDUFHOOHQXWVNRWW6HILJXU
'RSDPLQQHUYFHOOHUIULVlWWHUGRSDPLQWLOOV\QDSVHQLSXOVHUVRPVW\UVDYGHQHOHNWULVND
DNWLYLWHWHQLQHUYFHOOHQ1lUHQGRSDPLQQHUYFHOOlUDNWLYVNLFNDUGHQVQDEEWXWHQYLVV
PlQJG GRSDPLQ VRP VHGDQ VQDEEW WDV WLOOEDND LQ L FHOOHQ PHG KMlOS DY VSHFLHOOD
GRSDPLQWUDQVSRUW|UHU &HOOHQ VNLFNDU VHGDQ XW HQ Q\ ODGGQLQJ GRSDPLQ VRP RFNVn
VQDEEWWDVWLOOEDNDYDUSnGHWKHODXSSUHSDVLJHQ8QGHUGHQNRUWDWLGVRPGRSDPLQHW
EHILQQHUVLJLV\QDSVHQNDQGHWELQGDWLOOUHFHSWRUHUSnPRWWDJDUFHOOHQRFKSnYHUNDGHVV
DNWLYLWHW3nVnVlWWI|UVVLJQDOHQYLGDUHLKMlUQDQVQlWYHUN
0DQ WURU DWW DPIHWDPLQOLNQDQGH GURJHU IUDPNDOODU EHURHQGH GYV HWW WYnQJVPlVVLJW
LQWDJIUDPI|UDOOWJHQRPDWW|NDIULVlWWQLQJHQDYMXVWGRSDPLQ'HJ|UGHWWDJHQRPDWW
ELQGDWLOORFKEORFNHUDHOOHUWLOORFKPHGlQGUDULNWQLQJHQSnGRSDPLQWUDQVSRUW|UHUQDVn
DWWGRSDPLQHWOLJJHUNYDULV\QDSVHQEHW\GOLJWOlQJUHHIWHUDWWGHWIULVDWWVHOOHUIULVlWWV
WURWVDWWQHUYFHOOHQLQWHlUDNWLY1lUMDJE|UMDGHVWXGHUD7$$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$$5 SnYHUNDU
GRSDPLQSURGXNWLRQHQLQHUYFHOOHUVRPIULVlWWHUGRSDPLQ7DQNHQEDNRPGHWWDYDUDWW
HQ |NDG SURGXNWLRQ DY GRSDPLQ VDQQROLNW OHGHU WLOO HQ |NDG PlQJG GRSDPLQ VRP
IULVlWWVYLGYDUMHWLOOIlOOH'HWlUPHGDQGUDRUGLQWHEDUDKDVWLJKHWHQI|UIULVlWWQLQJRFK
nWHUXSSWDJ DY GRSDPLQ VRP VW\U VW\UNDQ Sn GRSDPLQVLJQDOHULQJHQ bYHQ PlQJGHQ
WLOOJlQJOLJW GRSDPLQ LQXWL GRSDPLQQHUYFHOOHQ SnYHUNDU VLJQDOHQ 9L VWXGHUDGH GHWWD
JHQRP DWW PlWD DNWLYLWHWHQ KRV GHW HQ]\P VRP VW\U KXU P\FNHW GRSDPLQ VRP
SURGXFHUDV 9L VnJ DWW XWDQ QnJRQ EHKDQGOLQJ DOOV YDU GRSDPLQSURGXNWLRQHQ K|JUH L
KMlUQYlYQDGIUnQP|VVVRPLQWHKDGH7$$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
/,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
&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$$5DFWLYDWLRQE\0'0$LQFUHDVHVW\URVLQHK\GUR[\ODVH
SKRVSKRU\ODWLRQDQGDFWLYLW\
&RQFOXGLQJUHPDUNV
&RQFOXVLRQV
3RWHQWLDOIXWXUHVWXGLHV
$FNQRZOHGJHPHQWV
5HIHUHQFHV
/,672)$%%5(9,$7,216
$'+'
$3'
$5-3
$73
ȕ3($
F$03
&16
&207
&5(%
&7[%
'$7
GEF$03
(5
(5$'
)&&6
)&6
)5$3
)5(7
*3&5
*5.
*67
+$
+VS
.2
/$$'&
/'+
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\OGLSKHQ\OWHWUD]ROLXPEURPLGH
QRUHSLQHSKULQHWUDQVSRUWHU
K\GUR[\GRSDPLQH
SDUDFKORURDPSKHWDPLQH
3DUNLQVRQ¶VGLVHDVH
SURWHLQNLQDVH$
SURWHLQNLQDVH&
SKRVSKROLSDVH$
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
,1752'8&7,21
6LQFH WKH LQLWLDO PDSSLQJ RI FDWHFKRODPLQHUJLF QHXURQV LQ WKH EUDLQ &DUOVVRQ HW DO
'DKOVWURHP )X[HLWKDVEHFRPHFOHDUWKDWFDWHFKRODPLQHUJLFVLJQDOLQJ
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\
VPDOOPROHFXOHVVXFKDVKRUPRQHVQHXURWUDQVPLWWHUVSHSWLGHVDQGOLSLGV*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
QHWZRUNV5LWWHU +DOO0RVWQRWDEO\ȕDUUHVWLQV)LJ&DQG*3&5NLQDVHV
*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\WKHUHFHSWRU5HLWHUHWDO6RPHDJRQLVWVWKXVKDYHDELDVWRZDUGV
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
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
&HQWUDO&DWHFKRODPLQHUJLF1HWZRUNV
7KHILUVWGHWDLOHGGHVFULSWLRQRIWKHGLVWULEXWLRQRIFDWHFKRODPLQHUJLFQHXURQVLQWKHUDW
&16 ZDV SXEOLVKHG LQ 'DKOVWURHP )X[H 'DKOVWU|P DQG )X[H WKHQ
LGHQWLILHGWZHOYHJURXSVRIFDWHFKRODPLQHUJLFFHOOV$$7RWKHVHILYHDGGLWLRQDO
FHOOJURXSV$$DQGWKUHHDGUHQDOLQHFRQWDLQLQJFHOOJURXSV&&ZHUHDGGHG
\HDUV ODWHU :LWK WKH GHYHORSPHQW RI QRYHO WHFKQLTXHV LW KDV EHFRPH SRVVLEOH WR
GLVWLQJXLVKEHWZHHQGLIIHUHQWFDWHFKRODPLQHV7KLVKDVOHGWRWKHGLVFRYHU\WKDWHDFKRI
GRSDPLQH QRUHSLQHSKULQH DQG HSLQHSKULQH DUH SURGXFHG E\ GLVWLQFW QHXURQV ZLWK
GHILQHGSURMHFWLRQVLQWKHEUDLQ)LJ
Figure 3: &DWHFKRODPLQHUJLF FHOOV DQG SURMHFWLRQV LQ WKH KXPDQ EUDLQ WRS DQG
FDWHFKRODPLQHUJLFFHOOJURXSVLQWKHPRXVHEUDLQERWWRP
&HOO JURXSV $$ 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
YHQWUDOWHJPHQWDODUHD97$$FRQWDLQWKHYDVWPDMRULW\RIGRSDPLQHUJLFQHXURQV
LQ WKH &16 DQG SOD\ FHQWUDO UROHV LQ 3DUNLQVRQ¶V GLVHDVH 3' SDWKRORJ\ DQG UHZDUG
VLJQDOLQJUHVSHFWLYHO\7ULWVFK 6DEDWLQL7KHPLGEUDLQGRSDPLQHUJLFQHXURQV
ZHUH WUDGLWLRQDOO\ VHSDUDWHG LQWR WZR PDMRU VXEW\SHV ZLWK GLVWLQFW SURMHFWLRQV WKH
QLJURVWULDWDOQHXURQVRIWKH$JURXSDQGWKH$QHXURQVSURMHFWLQJIURPWKH97$WR
OLPELFDQGFRUWLFDODUHDV0RUHUHFHQWO\WKLVKDVEHHQGHHPHGDQRYHUVLPSOLILFDWLRQ
to striatum
adrenaline noradrenaline dopamine
to spinal cord Locus coeruleus
Ventral tegmental area Substantia nigra
Medulla
A10A9A8 A11 A12 A13 A14 A15 A16
A1 A2 A5
A7 C2
C1 A6C3 A4
DQG PLGEUDLQ GRSDPLQH QHXURQV DUH LQVWHDG GLYLGHG LQWR D GRUVDO DQG D YHQWUDO WLHU
%MRUNOXQG 'XQQHWW7KHGRUVDOWLHULQFOXGHV$DQGWKHGRUVDOSDUWRI$DQG
$ DQG WKH YHQWUDO WLHU LQFOXGHV WKH YHQWUDO SDUWV RI $ DQG $ 1HXURQV LQ WKH
GRUVDOWLHUH[WHQGWKHLUD[RQVWRYHQWUDOVWULDWDOFRUWLFDODQGOLPELFDUHDV%MRUNOXQG 'XQQHWW 7KHVH PHVRFRUWLFROLPELF GRSDPLQH SURMHFWLRQV GLUHFW UHVSRQVHV WR
UHZDUG DQG DUH LQYROYHG LQ GHSUHVVLYH V\PSWRPV DV ZHOO DV DIIHFWHG E\ PDQ\
SV\FKRVWLPXODQWV 1HXURQV LQ WKH YHQWUDO 61 H[WHQG WKHLU D[RQV H[FOXVLYHO\ WR WKH
VWULDWXP %MRUNOXQG 'XQQHWW 7KLV QLJURVWULDWDO SDWKZD\ LV LQVWUXPHQWDO LQ
UHJXODWLRQRIPRWRUIXQFWLRQDQGVWURQJO\DIIHFWHGLQ3'1HXURQVLQWKHYHQWUDO97$
DOVRH[FOXVLYHO\SURMHFWWRWKHVWULDWXPDQGDUHOLNHZLVHLQYROYHGLQUHJXODWLRQRIPRWRU
IXQFWLRQEXWDIIHFWHGWRDORZHUH[WHQWLQ3'%MRUNOXQG 'XQQHWW
$OOQRUDGUHQHUJLFFHOOJURXSV$$DUHORFDWHGLQQXFOHLZLWKLQWKHSRQVDQG
WKHPHGXOODREORQJDWD.YHWQDQVN\HWDO6P\WKLHV)RXURIWKHVHJURXSV
$$$DQG$DUHORFDWHGZLWKLQWKHORFXVFRHUXOHXV.YHWQDQVN\HWDO
6P\WKLHV DQG H[WHQG DVFHQGLQJ SURMHFWLRQV WR WKH IRUHEUDLQ LQFOXGLQJ WKH
K\SRWKDODPXVFHUHEUDOFRUWH[DQGOLPELFV\VWHPDQGWKHFHUHEHOOXP&HOOJURXSV$
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 6HZHOO1RUDGUHQDOLQHUHOHDVHDSSHDUVWREHWKH PDLQHIIHFWRURI
VXEMHFWLYHUHZDUGDQGUHODSVHLQSV\FKRVWLPXODQWDGGLFWLRQ6RIXRJOX 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
''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%\OXQGHWDO5HFHSWRUVRI
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\FODVH6RIXRJOX 6HZHOO7KHVHUHFHSWRUVDUHORFDWHG
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.XKDUHWDODQGDGUHQDOLQHDQGQRUDGUHQDOLQHDUHWDNHQXS
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¶VGLVHDVH3'LVWKHVHFRQGPRVWIUHTXHQWQHXURGHJHQHUDWLYHGLVRUGHUDIWHU
$O]KHLPHU¶VGLVHDVHDIIHFWLQJDERXWRIWKHSRSXODWLRQRYHU\HDUVRIDJH/HHV
HWDO$SDWKRORJLFDOKDOOPDUNDQGFDXVHRIPRVWV\PSWRPVLVWKHSURJUHVVLYH
GHDWK RI FDWHFKRODPLQHUJLF QHXURQV 7KLV PDLQO\ LQYROYHV QLJURVWULDWDO GRSDPLQHUJLF
QHXURQVEXWGHJHQHUDWLRQRIROIDFWRU\QHXURQVDQGQRUDGUHQHUJLFQHXURQVLQWKHORFXV
FRHUXOHXVLVDOVRREVHUYHGDOUHDG\DWDQHDUO\VWDJHRIGLVHDVH/HHVHWDO3'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
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
HUJROLQHGRSDPLQHDJRQLVWVVXFKDVSUDPLSH[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
'RSDPLQHUJLFQHXURQVRIWKHVXEVWDQWLDQLJUDSDUVFRPSDFWD61SFUHSUHVHQWWKHYDVW
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'RXEOHHWDO7KHLGHDWKDWR[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[ ,
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 $73 7KH\ DOVR IXQFWLRQ LQ
PDLQWHQDQFHRIFHOOXODU&DKRPHRVWDVLVDQGLQOLSLGDPLQRDFLGFDUERK\GUDWHDQG
VWHURLGPHWDEROLVP0DUWLQH] *UHHQDP\UH,QDGGLWLRQWRLPSDLUHGFRPSOH[,
DFWLYLW\DQLQFUHDVHGQXPEHURIGHOHWLRQVWR PLWRFKRQGULDO'1$PW'1$KDVEHHQ
REVHUYHG SRVWPRUWHP LQ WKH 61SF RI 3' SDWLHQWV 0DUWLQH] *UHHQDP\UH
6FKRQ 3U]HGERUVNL 6XFK GHOHWLRQV DUH OLNHO\ WR OHDG WR D ODUJHU IUDFWLRQ RI
IDXOW\ PLWRFKRQGULD WKDW PD\ GLVUXSW FHOOXODU KRPHRVWDVLV ERWK WKURXJK ORVV RI WKHLU
QRUPDO IXQFWLRQ DQG WKURXJK H[FHVVLYH 526 SURGXFWLRQ 'DPDJHG PLWRFKRQGULD DUH
HOLPLQDWHG E\ WKH FHOO WKURXJK PLWRFKRQGULDO DXWRSKDJ\ PLWRSKDJ\ RU LQFRUSRUDWHG
LQWRIXQFWLRQDOPLWRFKRQGULDWKURXJKPLWRFKRQGULDOIXVLRQWRDWWHQXDWHWKHLUGHOHWHULRXV
HIIHFWV6FKRQ 3U]HGERUVNL$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
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(5WKHXQIROGHGSURWHLQUHVSRQVH835RU(5VWUHVVUHVSRQVHLV
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+VSLQDrosophilaRYHUH[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 7DNDKDVKLDQGRYHUH[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:DQJHWDOE7KH
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.
3DUNLQWKHXELTXLWLQK\GURODVH8&+/DQGĮV\QXFOHLQ(EUDKLPL)DNKDULHWDO
5RVV 3RLULHU $JJUHJDWLRQ SURQH ĮV\QXFOHLQ PXWDQWV LQKLELW SURWHDVRPH
IXQFWLRQOHDGLQJWRLQFUHDVHGDSRSWRVLV6WHIDQLVHWDO7DQDNDHWDODQG
V\VWHPLF WUHDWPHQW ZLWK SURWHDVRPH LQKLELWRUV FDQ FDXVH 3DUNLQVRQLVP LQ URGHQWV
(EUDKLPL)DNKDULHWDO0XWDQWĮV\QXFOHLQDOVRLQKLELWVDXWRSKDJ\&XHUYRHW
DO DQG ĮV\QXFOHLQ ROLJRPHUV SDUWLFLSDWH LQ D SDWKRJHQLF F\FOH ZKHUH WKH\
LQKLELWQRUPDOO\VRVRPDOIXQFWLRQZKLFKLQWXUQSURPRWHVIXUWKHUDFFXPXODWLRQRIĮ
V\QXFOHLQROLJRPHUV0D]]XOOLHWDO$QLQFUHDVHRIDXWRSKDJRVRPHVKDVEHHQ
REVHUYHG LQ WKH 61 RI 3' SDWLHQWV LQGLFDWLQJ HLWKHU RYHUSURGXFWLRQ RU LPSDLUHG
WXUQRYHURIDXWRSKDJRVRPHV$QJODGHHWDO7KHUHLVDOVRHYLGHQFHIRUUHGXFHG
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
HWDO5HVXOWVIURPVWXGLHVLQDQLPDOPRGHOVDOVRVXJJHVWWKDW0373URWHQRQHRU
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