title: NRSF is an essential mediator for the neuroprotection of trichostatin A in the MPTP mouse model of Parkinson's disease.
abstract: Neuron-restrictive silencer factor (NRSF) blocks the expression of many neuronal genes in non-neuronal cells and neural stem cells. There is growing body of evidence that NRSF functions in mature neurons and plays critical roles in various neurological disorders. Our previous study demonstrated that the expression of NRSF target genes brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) is transiently decreased in 1-methyl-4-phenyl-pyridinium ion (MPP+)-treated SH-SY5Y cells. NRSF neuronal deficient mice are more vulnerable to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we investigated the effect of epigenetic modulation on the expression of NRSF target genes in in vitro and in vivo models of Parkinson's disease (PD). Trichostatin A (TSA) was further used to study the effects of histone deacetylase inhibition on NRSF-mediated repression. We found that the repression of NRSF target genes was relieved by TSA in vitro. A single dose TSA pretreatment also upregulated the expression of TH and BDNF and protected the nigrostriatal dopaminergic pathway against MPTP-induced degeneration in wild type mice. However, the protective functions of TSA were fully abolished in NRSF neuronal deficient mice. Our results suggest that NRSF serves as an essential mediator for the neuroprotection of TSA in the MPTP model of PD.
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Suo
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Tong
authors.affiliation: Shanghai Research Center for Model Organisms, Pudong, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Dongping
authors.initials: D
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Zishan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China. Electronic address: yumei@fudan.edu.cn.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China; Shanghai Research Center for Model Organisms, Pudong, Shanghai 201203, China. Electronic address: jfei@mail.tongji.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
authors.affiliation: The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China; Key Laboratory of Smart Drug Delivery, Fudan University, Ministry of Education, Shanghai 201203, China. Electronic address: huangf@shmu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D044127:Epigenesis, Genetic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006657:Histones; D006877:Hydroxamic Acids; D006897:Hydroxyindoleacetic Acid; D018696:Neuroprotective Agents; D012097:Repressor Proteins; D012701:Serotonin; D000099229:RE1-Silencing Transcription Factor; C012589:trichostatin A
keywords: Epigenetic mechanisms; HDAC inhibitors; NRSF; Parkinson's disease; Target genes