Induction of apoptosis signal-regulating kinase 1 and oxidative stress mediate age-dependent vulnerability to 3-nitropropionic acid in the mouse striatum.
The mitochondrial toxin, 3-nitropropionic acid (3-NP), produces age-dependent oxidative stress and selective striatal damage, which may simulate Huntington's disease starting in middle age. Recent reports showed that apoptosis signal-regulating kinase 1 (Ask1) activated by oxidative stress triggers a cell death signaling pathway. 3-NP was injected to the striatum in C57BL/6J mice. We have confirmed that striatal lesion volume and DNA fragmentation were age-dependent after 3-NP treatment. In the non-injured striatum of the middle-aged group, the protein levels of Ask1 and its active form, phosphorylated Ask1 (pAsk1), were significantly higher than in the young group. Ask1 increased more in the 3-NP injured striatum of the middle-aged group than in the non-injured striatum, and subsequently the activity of pAsk1 was significantly higher than in the young group. However, middle-aged SOD1Tg mice showed significant reductions of Ask1 and pAsk1 in the injured and the non-injured striatum compared to the middle-aged group. In particular, apoptosis signal transduction and cell death were significantly inhibited by the reduction of Ask1 expression using siRNA. Present results suggest that age-related upregulation of Ask1 and oxidative stress may mediate age-dependent striatal vulnerability to 3-NP.
Hangang Sacred Heart Hospital, Department of Neurology, Hallym University, South Korea.
Yangki
Y
Minn
Kyoung-Joo
KJ
Cho
Hyun-Woo
HW
Kim
Hyun-Jeong
HJ
Kim
Seung-Han
SH
Suk
Byung I
BI
Lee
Gyung W
GW
Kim
D000375:Aging / Q000502:physiology*; D000818:Animals; D003292:Convulsants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009574:Nitro Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D003292:Convulsants; D007211:Indoles; D009574:Nitro Compounds; D011422:Propionates; D034741:RNA, Small Interfering; C007293:DAPI; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C015392:3-nitropropionic acid