NRSF - Mediated Apparent Modification Of Silencing In Parkinson 's Disease

Part1Parkinson’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-1silencing transcription factor (REST), a member of the zinc finger transcription factors, inhibits the expression of neuron-specific genes in non-neuronal cells, and regulates neurogenesis. Our previous work showed that1-methyl-4-phenyl-pyridinium ion (MPP+) triggers dynamic changes of mRNA and protein expression of NRSF/REST in human dopaminergic SH-SY5Y cells, and alteration of NRSF/REST expression exacerbates MPP+-induced cell death. The purpose of this study was to explore the in vivo role of NRSF/REST 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. We found the reduction of tyrosine hydroxylase (TH) protein in the striatum and the loss of dopaminegic neurons in the substantia nigra were more severe in the cKO mice. Meanwhile, the cKO mice exhibited a more dramatic depletion of the striatal dopamine, accompanied by an increase in glial fibrillary acidic protein (GFAP) expression and sustained IL-1(5transcription. These results suggested that NRSF/REST neuronal conditional knockout mice are more vulnerable to the dopaminergic neurotoxin MPTP. Disturbance of the homeostasis of NRSF/REST and its target genes, gliogenesis, and inflammation may contribute to the higher MPTP senstitivity in NRSF/REST neuronal conditional knockout mice. Neuron-restrictive silencer factor/Repressor element1silencing transcription factor (NRSF/REST) blocks the expression of many neuronal genes in non-neuronal and neural stem cells. NRSF modulates the expression of target genes through interactions with other corepressors and chromatin remodeling complexes.Our previous study showed that the expression of NRSF/REST target gene BDNF, TH, Synapsin I and UCH-L1were transiently decreased in PD cell model, NRSF/REST neuronal deficient mice were more vulnerable to the neurotoxin MPTP. Here we investigated the effect of epigenetic modulation on the expression of NRSF/REST target genes in in vitro and in vivo PD models. Trichostatin A (TSA), a well-characterized, potent inhibitor of HDACs, was further used to study the effects of HDAC inhibition on NRSF/REST-mediated repression. In SH-SY5Y cells, MPP+intoxication increased the binding of NRSF/REST to its target genes; concomitantly, the epigenetic patterns of histones around the NRSE/RE1sites were also altered. MPP+-induced, NRSF/REST-mediated repression of target genes was relieved by TSA in vitro, while intraperitoneal injection of TSA preserved the nigrostriatal dopamine pathway from MPTP-induced degeneration in vivo.However, the protective roles of TSA on dopaminergic neurons were disappeared in NRSF/REST neuronal deficient mice. Our results demonstrate that NRSF/REST represses its target gene expression in Parkinson’s disease via an HDAC-dependent pathway and the cross-talk between acetylation and methylation of histones around the RE1sites. NRSF/REST serves as a mediator for the neuroprotection of TSA in MPTP mouse PD model.