Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo.

Proc Natl Acad Sci U S A

Department of Environmental Health, Rollins School of Public Health,Department of Pharmacology,Department of Neurology,Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;

Published: July 2014

AI Article Synopsis

  • Disruption in the dynamics of neurotransmitter vesicles is linked to various neurodegenerative and neuropsychiatric disorders, prompting the exploration of a new mouse model with enhanced vesicular function through VMAT2 overexpression.
  • This model demonstrated significant improvements, including a 56% increase in dopamine transport capacity, a 21% rise in tissue dopamine levels, and an 84% boost in stimulated dopamine release, alongside enhanced locomotor activity and reduced anxiety/depressive behaviors.
  • Additionally, these mice showed protection against neurotoxicity from MPTP, indicating that therapies aimed at boosting vesicular capacity may offer new treatment options for conditions like Parkinson's disease.

Article Abstract

Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103325PMC
http://dx.doi.org/10.1073/pnas.1402134111DOI Listing

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