TARGETING FREE RADICALS: A VALID THERAPEUTIC APPROACH FOR HUNTINGTON’S DISEASE?

P5 TARGETING FREE RADICALS: A VALID THERAPEUTIC APPROACH FOR HUNTINGTON’S DISEASE? Marie-Françoise Chesselet1, Aroa Relano-Gines1, Catherine F. Clarke1, and Mikhail S. Shchepinov2, 1UCLA, USA, 2Retrotope, USA 0LWRFKRQGULDOG\VIXQFWLRQDQGLQFUHDVHGR[LGDWLYHVWUHVVKDYHEHHQLQFULPLQDWHGLQ+XQ WLQJWRQ¶VGLVHDVH+' DQLQFXUDEOHQHXURGHJHQHUDWLYHGLVRUGHUGXHWRDQH[SDQGHG&$* UHSHDWLQWKHJHQHHQFRGLQJKXQWLQJWLQ+'DVVRFLDWHGLQFUHDVHGDFWLYLW\RI1$'3+R[L GDVH12; DFWLYLW\LQOLSLGUDIWVPD\LQFUHDVHOLSLGSHUR[LGDWLRQSULPDULO\RISRO\XQVDWX UDWHGIDWW\DFLGV38)$ WKDWDUHDEXQGDQWLQV\QDSWLFDQGPLWRFKRQGULDOPHPEUDQHV RUPRUHRIWKHWRWDOOLSLGV 3UHYLRXVVWXGLHVKDYHVKRZQWKDWDVPDOOa IUDFWLRQRI LVRWRSHUHLQIRUFHG 38)$ '38)$  PL[HG ZLWK DQ\ QRQGHXWHUDWHG 38)$ SURIRXQGO\ LQ KLELWVOLSLGSHUR[LGDWLRQDQGKDVQHXURSURWHFWLYHHIIHFWVLQPRGHOVRIQHXURGHJHQHUDWLYH GLVHDVHVVXFKDV3DUNLQVRQ¶VGLVHDVHDQG)ULHGUHLFK$WD[LD:HWHVWHGWKHK\SRWKHVLV WKDW'38)$LQKLELWPHPEUDQHDVVRFLDWHGR[LGDWLYHVWUHVVLQD PRXVHVWULDWDO67Hdh4 4 FHOO OLQHV /7KRPSVRQ 8&,  GHULYHG IURP WKH PRXVH VWULDWXP RI 4 NQRFNLQ .,  +'PLFHDQGE 1HXURVSKHUHV1) GHULYHGIURPWKHVXEYHQWULFXODU]RQH69= RIWKH ODWHUDOYHQWULFOHVRUVXEJUDQXODU]RQH6*= RIWKHKLSSRFDPSXVRI4.,PLFHDQGWKHLU UHVSHFWLYH ZLOGW\SH FRXQWHUSDUWV '/QQ DW  μ0 DQG '/LQ DW μ0 GHFUHDVHG OLSLG SHUR[LGDWLRQFRPSDUHGWRYHKLFOHLQWKH67Hdh44 FHOOVZLWKRXWUHGXFLQJFHOOYLDELOLW\ /LSLGSHUR[LGDWLRQOHYHOVZHUHHOHYDWHGLQ1)IURP6*=DQG69=RI4.,PLFHFRP SDUHGWRZLOGW\SHOLWWHUPDWHVIXUWKHUVXSSRUWLQJDUROHIRUOLSLGSHUR[LGDWLRQLQ+''/LQ DQG'/QQUHGXFHGOLSLGSHUR[LGDWLRQLQ1)IURPERWKUHJLRQVDJDLQZLWKRXWGHWULPHQWDO HIIHFWVRQYLDELOLW\7KHUHVXOWVVXJJHVWWKDWWKLVQRYHOQRQDQWLR[LGDQWEDVHGDSSURDFK KDVSRWHQWLDOIRUWKHWUHDWPHQWRI+'DQGVKRXOGQH[WEHWHVWHGLQPRXVHPRGHOVRI+' 6XSSRUW+HUHGLWDU\'LVHDVH)RXQGDWLRQ

Marie-Françoise Chesselet

doi: 10.1016/j.freeradbiomed.2014.10.015

P6 ELEVATED OXIDATIVE STRESS IN MOTOR NEURONS INITIATES LOSS OF NEUROMUSCULAR JUNCTION STRUCTURE AND FUNCTION, MUSCLE WEAKNESS AND ATROPHY Holly Van Remmen, Oklahoma Medical Research Foundation, USA 2XUVWXGLHVGHPRQVWUDWHWKDW\RXQJDGXOWPLFHODFNLQJWKHVXSHUR[LGHDQLRQVFDYHQJHU &X=Q62' Sod1-/-PLFH  H[KLELW DJHUHODWHG PXVFOH DWURSK\ZHDNQHVV WKDW FORVHO\ PLP LFV WKH VDUFRSHQLD SKHQRW\SH RI ROG ZLOG W\SH PLFH LQFOXGLQJ 10- GHJHQHUDWLRQ PRWRU QHXURQ UHWUDFWLRQ DQG HOHYDWHG PXVFOH PLWRFKRQGULDO 526 JHQHUDWLRQ &RQYHUVHO\ PLFH ODFNLQJ 0Q62' 7Q,&UHSod2-/-  RU &X=Q62' PSod1-/-  WDUJHWHG VSHFL¿FDOO\ WR VNHOHWDO PXVFOH VKRZ QR ORVV RI PXVFOH PDVV LPSOLFDWLQJ QHXURQDO VWUHVV DV WKH SULPDU\ LQLWLD WRURIPXVFOHDWURSK\7RWHVWWKHUROHRISUHV\QDSWLFR[LGDWLYHVWUHVVLQWKHLQLWLDWLRQRI PXVFOHDWURSK\DQGGHJHQHUDWLRQRIWKHQHXURPXVFXODUMXQFWLRQ10- ZHJHQHUDWHG³UHV FXH´PLFHSynTgSod1-/- PLFH WKDWH[SUHVV&X=Q62'LQEUDLQVSLQDOFRUGDQGSHULSKHUDO QHUYHVEXWQRWRWKHUWLVVXHV,QFRQWUDVWWRSod1-/- PLFH SynTgSod1-/- PLFH GR QRW VKRZ ORVV RI PXVFOH PDVV RU PD[LPXP LVRPHWULF VSHFL¿F IRUFH SURGXFWLRQ DW  PRQWKV RI DJH ZKHQ VLJQL¿FDQW ORVVHV DUH HYLGHQW LQ Sod1-/- PLFH $FFHOHUDWHG GHJHQHUDWLRQ LQ 10VWUXFWXUH DQG IXQFWLRQ WKDW LV SURPLQHQW LQ WKH Sod1-/- PLFH GRHV QRW RFFXU LQ SynTgSod1-/PLFH Sod1-/- PLFH GHPRQVWUDWH UHGXFHG VFLDWLF PRWRU FRQGXFWLRQ YHORFLW\ DQG SDWKRORJL FDO GHFUHPHQW ! LQ FRPSRXQG PXVFOH DFWLRQ SRWHQWLDO &0$3 DPSOLWXGH LQGLFDWLYH RI D[RQRSDWK\ WKDW DUH QRW SUHVHQW LQ SynTgSod1-/- PLFH 7KXV SURWHFWLRQ IURP R[LGDWLYH VWUHVV LQ QHXURQV SUHVHUYHV VNHOHWDO PXVFOH DQG 10- VWUXFWXUH DQG IXQFWLRQ 'HOHWLRQ RI Sod1 DQG LQGXFWLRQ RI R[LGDWLYH VWUHVV LQ HLWKHU QHXURQV RU VNHOHWDO PXVFOH DORQH GRHV QRW UHSOLFDWH WKH IXOO VDUFRSHQLD SKHQRW\SH RI WKH Sod1-/- PLFH VXJJHVWLQJ DQ LQWHUDFWLYH HI IHFW EHWZHHQ WKH WZR WLVVXHV 2XU IXWXUH VWXGLHV ZLOO GHWHUPLQH ZKHWKHU QHXURQDO LQLWLDWLRQ RI 10- GLVUXSWLRQ LV VXI¿FLHQW IRU PXVFOH DWURSK\ZHDNQHVV RU LI DGGLWLRQDO DOWHUDWLRQV LQ PXVFOH R[LGDWLYH VWUHVV DUH UHTXLUHG WR LQGXFH WKH SKHQRW\SH doi: 10.1016/j.freeradbiomed.2014.10.016

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Holly Van Remmen