Brain-specific NRSF deficiency aggravates dopaminergic neurodegeneration and impairs neurogenesis in the MPTP mouse model of Parkinson's disease.

Dongping Huang,Yuanyuan Ma,Zishan Wang,Fang Huang,Qing Li,Zhaolin Liu,Yi Wang,Jing Su,Mei Yu,Jian Fei,Heng Li,Jinghui Wang

doi:10.18632/aging.101979

Abstract

Degeneration of the dopaminergic neurons in the substantia nigra and the resultant dopamine depletion from the striatum are the hallmarks of Parkinson’s disease (PD) and are responsible for the disease’s cardinal motor symptoms. The transcriptional repressor Neuron-Restrictive Silencer Factor (NRSF), also known as RE1-Silencing Transcription Factor (REST), was originally identified as a negative regulator of neuron-specific genes in non-neuronal cells. Our previous study showed that mice deficient in neuronal NRSF/REST expression were more vulnerable to the noxious effects of the dopaminergic neurotoxin MPTP. Here, we found that brain-specific deletion of NRSF/REST led to more severe damages to the nigrostriatal pathway and long-lasting behavioral impairments in mice challenged with MPTP. Moreover, compared to wild-type controls, these mice showed increased neurogenesis shortly after MPTP exposure, but reduced neurogenesis later on. These results suggest that NRSF/REST acts as a negative modulator of neurogenesis and a pro-survival factor of neural stem cells under both normal conditions and during the course of PD.

Highlights

Progressive loss of dopaminergic neurons in the substantia nigra par compacta (SNpc) with resultant dopamine depletion in the striatum characterizes Parkinson’s disease (PD) and accounts for the disease’s cardinal motor symptoms [1]
The evidence for adult neurogenesis stems from the discovery of neuronal precursor cells (NPCs) in the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, that retain the capacity of producing www.aging-us.com new neurons both in health and disease
We previously showed that injuries in the nigrostriatal pathway induced by the neurotoxin MPTP were more severe in neuronal Neuron-Restrictive Silencer Factor (NRSF) deficient mice than in WT mice [19, 20]

Summary

Introduction

Progressive loss of dopaminergic neurons in the substantia nigra par compacta (SNpc) with resultant dopamine depletion in the striatum characterizes Parkinson’s disease (PD) and accounts for the disease’s cardinal motor symptoms [1]. Current therapeutic strategies are mostly based on pharmacological enhancement of dopaminergic neurotransmission. The evidence for adult neurogenesis stems from the discovery of neuronal precursor cells (NPCs) in the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, that retain the capacity of producing www.aging-us.com new neurons both in health and disease. This phenomenon was first described in 1962 by J. Over the past few years, scientists assessed a massive set of genes, miRNAs, and transcription factors to evaluate their potential influence on neurogenesis and aid the development of new therapies for neurodegenerative diseases

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Conclusion