Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice.

Study Authors Hui Shen and Rosa Anna Maria Marino

Hot Off the Press – November 29, 2018.

The neural mechanisms underlying dopamine neuron degeneration in Parkinson’s disease are largely unknown. In this study, we found that selective deletion of a vesicular glutamate transporter (VgluT2) in dopamine neurons led to a significant increase in dopamine neuron toxicity to the neurotoxin MPTP via a BDNF-dependent mechanism, suggesting that reduced VgluT2 expression in dopamine neurons may constitute a risk factor in the development of Parkinson’s disease.

Publication Information

Shen, Hui; Marino, Rosa Anna M; McDevitt, Ross A; Bi, Guo-Hua; Chen, Kai; Madeo, Graziella; Lee, Pin-Tse; Liang, Ying; Biase, Lindsay M De; Su, Tsung-Ping; Xi, Zheng-Xiong; Bonci, Antonello

Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice. Journal Article

In: Proc Natl Acad Sci U S A, 2018, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking).

Abstract | Links

@article{Shen:2018aa,

title = {Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice.},

author = {Hui Shen and Rosa Anna M Marino and Ross A McDevitt and Guo-Hua Bi and Kai Chen and Graziella Madeo and Pin-Tse Lee and Ying Liang and Lindsay M De Biase and Tsung-Ping Su and Zheng-Xiong Xi and Antonello Bonci},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30442663},

doi = {10.1073/pnas.1800886115},

issn = {1091-6490 (Electronic); 0027-8424 (Linking)},

year  = {2018},

date = {2018-11-15},

journal = {Proc Natl Acad Sci U S A},

address = {Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224.},

abstract = {A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}