title: NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP.
abstract: Parkinson's disease (PD) is characterized by progressing loss of dopaminergic neurons in the midbrain. Abnormal gene expression plays a critical role in its pathogenesis. Neuron-restrictive silencer factor (NRSF)/neuronal repressor element-1 silencing transcription factor (REST), a member of the zinc finger transcription factors, inhibits the expression of neuron-specific genes in nonneuronal cells, and regulates neurogenesis. Our previous work showed that 1-methyl-4-phenyl-pyridinium ion triggers dynamic changes of messenger RNA and protein expression of NRSF in human dopaminergic SH-SY5Y cells, and alteration of NRSF expression exacerbates 1-methyl-4-phenyl-pyridinium ion-induced cell death. The purpose of this study was to explore the in vivo role of NRSF in the progress of PD by using NRSF/REST neuron-specific conditional knockout mice (cKO). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in the cKO mice and wild type littermates. At 1, 3, 7, 14, 21, and 28 days after MPTP injection, behavioral tests were performed, and cKO mice displayed some impairments in locomotor activities. Also, the reduction of tyrosine hydroxylase protein in the striatum and the loss of dopaminergic neurons in the substantia nigra were more severe in the cKO mice. Meanwhile, the cKO mice exhibited a more dramatic depletion of striatal dopamine, accompanied by an increase in glial fibrillary acidic protein (GFAP) expression and sustained interleukin-1β transcription. These results suggested that NRSF/REST neuronal cKO mice are more vulnerable to the dopaminergic neurotoxin MPTP. Disturbance of the homeostasis of NRSF and its target genes, gliogenesis, and inflammation may contribute to the higher MPTP sensitivity in NRSF/REST neuronal cKO mice.
authors: State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Mei
authors: M
authors: Yu
authors: Haiyun
authors: H
authors: Suo
authors: Ming
authors: M
authors: Liu
authors: Lei
authors: L
authors: Cai
authors: Jie
authors: J
authors: Liu
authors: Yufang
authors: Y
authors: Huang
authors: Jing
authors: J
authors: Xu
authors: Yancong
authors: Y
authors: Wang
authors: Cuiqing
authors: C
authors: Zhu
authors: Jian
authors: J
authors: Fei
authors: Fang
authors: F
authors: Huang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D009498:Neurotoxins / Q000009:adverse effects*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009498:Neurotoxins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor