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Neurotherapeutics. 2016 Jul;13(3):623-34. doi: 10.1007/s13311-016-0435-5.

hVMAT2: A Target of Individualized Medication for Parkinson's Disease.

Author information

1
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
2
School of Life Sciences, Beijing Institute of Technology, 100081, Beijing, China.
3
Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA.
4
Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
5
Tianjin Mental Health Center, Tianjin Anding Hospital, 300222, Tianjin, China.
6
Bio-Organic and Nutritional Products Laboratory, McLean Hospital, Belmont, MA, 02478, USA.
7
Neuroregeneration Laboratories, McLean Hospital, Belmont, MA, 02478, USA.
8
Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA. zhicheng_lin@hms.harvard.edu.

Abstract

Vesicular monoamine transporter 2 (VMAT2) is responsible for sequestering cytosolically toxic dopamine into intracellular secretory vesicles. Animal genetic studies have suggested that reduced VMAT2 activity contributes to the genetic etiology of Parkinson's disease (PD), but this role has not been established in humans. Based on human genetic association and meta-analysis, we first confirm the human VMAT2 (hVMAT2 or SLC18A2) promoter as a risk factor for PD in both family and unrelated US white people: marker rs363324 at -11.5 kb in the hVMAT2 promoter is reproducibly associated with PD in a cohort of nuclear families (p = 0.04506 in early-onset PD) and 3 unrelated US white people (meta-analysis p = 0.01879). In SH-SY5Y cells, low activity-associated hVMAT2 promoter confers high methylpiperidinopyrazole iodide cytotoxicity, which is likely attributed to functional polymorphisms bound by nuclear proteins. Interestingly, treatments with the dopamine neuron-protecting agent puerarin upregulates the promoter activity in a haplotype- and cell line-dependent manner. These pharmacogenetic findings suggest that hVMAT2 could be a risk factor and imply it as a target of genetic medications for PD.

KEYWORDS:

Association; Epigenetics; Haplotypic toxicity; Haplotypic upregulation; Meta-analysis; SLC18A2; Vesicular monoamine transporter 2

PMID:
27137201
PMCID:
PMC4965405
DOI:
10.1007/s13311-016-0435-5
[Indexed for MEDLINE]
Free PMC Article

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