hVMAT2: A Target of Individualized Medication for Parkinson’s Disease

Nian Xiong, Nuomin Li, Eden Martin, Jinlong Yu, Jie Li, Jing Liu, David Yue Wei Lee, Ole Isacson, Jeffery Vance, Hong Qing, Tao Wang, Zhicheng Lin

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)623-634
Number of pages12
JournalNeurotherapeutics
Volume13
Issue number3
DOIs
StatePublished - Jul 1 2016

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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  • Cite this

    Xiong, N., Li, N., Martin, E., Yu, J., Li, J., Liu, J., Lee, D. Y. W., Isacson, O., Vance, J., Qing, H., Wang, T., & Lin, Z. (2016). hVMAT2: A Target of Individualized Medication for Parkinson’s Disease. Neurotherapeutics, 13(3), 623-634. https://doi.org/10.1007/s13311-016-0435-5