Intestinal Dopamine Receptor D2 is Required for Neuroprotection Against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Dopaminergic Neurodegeneration

Hairong Peng1,2 • Shui Yu1,2 • Yukai Zhang1,2 • Yanqing Yin1 • Jiawei Zhou1,2,3

1 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China

2 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China

3 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China

 

Abstract

A wealth of evidence has suggested that gastrointestinal dysfunction is associated with the onset and progression of Parkinson’s disease (PD). However, the mechanisms underlying these links remain to be defined. Here, we investigated the impact of deregulation of intestinal dopamine D2 receptor (DRD2) signaling in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration. Dopamine/dopamine signaling in the mouse colon decreased with ageing. Selective ablation of Drd2, but not Drd4, in the intestinal epithelium, caused a more severe loss of dopaminergic neurons in the substantia nigra following MPTP challenge, and this was accompanied by a reduced abundance of succinate-producing Alleoprevotella in the gut microbiota. Administration of succinate markedly attenuated dopaminergic neuronal loss in MPTP-treated mice by elevating the mitochondrial membrane potential. This study suggests that intestinal epithelial DRD2 activity and succinate from the gut microbiome contribute to the maintenance of nigral DA neuron survival. These findings provide a potential strategy targeting neuroinflammationrelated neurological disorders such as PD.

 

Keywords

    Intestine; DRD2; Parkinson’s disease; MPTP; Succinate; Mitochondria

 

 

[SpringerLink]