Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo.
Parkinson's disease (PD) has been proposed to result from a combination of genetic susceptibility and environmental exposure. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in neuron degeneration and in pathogenesis of PD. Nurr1, a member of nuclear receptor superfamily, is a potential susceptibility gene for PD. In this in vitro and in vivo study, we investigated whether Nurr1 deficiency may predispose to environmental proteasome inhibitors-induced neuron injury. We found that lactacystin, an irreversible proteasome inhibitor, caused greater injury to SH-SY5Y cells that Nurr1 expression has been suppressed by small interference RNA (siRNA). On the contrary, the Nurr1 overexpressed SH-SY5Y cells by Nurr1 expression vector transfection rescued the lactacystin-induced injury. In vivo, stereotactic microinjection with lactacystin into right median forebrain bundle (MFB) of mice caused significant inhibition of the proteasome activity in both Nurr1 knock out heterozygous (Nurr1 +/-) mice and their littermate wild-type (Nurr1 +/+) mice. At same time, we found that there was a severer loss of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) and greater reduction of striatal dopamine (DA) levels in Nurr1 +/- mice as compared with that in Nurr1 +/+ mice. Furthermore, lactacystin-induced increase of cleaved PARP, cleaved caspase3 and p53 and decrease of bcl-2 in SN was significantly enhanced in Nurr1 +/- mice. These findings suggest that reduction in Nurr1 expression increases susceptibility to DAergic neuron injury induced by UPS impairment.
Pan
Tianhong
T
Parkinson's Disease Research Laboratory, Baylor College of Medicine, 6501 Fannin Street, Houston, TX 77030, USA.
Zhu
Wen
W
Zhao
Hongru
H
Deng
Hao
H
Xie
Wenjie
W
Jankovic
Joseph
J
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001930:Brain Injuries / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015984:Causality; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000172:deficiency*; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014157:Transcription Factors; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine; D000111:Acetylcysteine