Enhancing Vesicular Packaging May Offer New Therapeutic Target for Parkinson's
Gary Miller, Ph.D.; Amy Dunn; Alison Bernstein, Ph.D.
NIEHS Grants P01ES016731, P30ES019776, T32ES012870
NIEHS grantees report that mice genetically engineered to overexpress a protein involved in packaging the neurotransmitter dopamine showed higher levels of dopamine neurotransmission and were protected from a neurotoxin that causes permanent symptoms of Parkinson's disease. The findings point to a possible new therapeutic target for Parkinson’s disease, which is associated with the loss of dopamine-producing neurons.
Vesicular monoamine transporter 2 (VMAT2) is a protein that packages dopamine and other monoamine neurotransmitters into vesicles for later release by neurons. Recent research has shown that VMAT2 function is impaired in people with Parkinson’s disease. To learn more about the potential benefits of increasing VMAT2 function, the researchers generated transgenic mice with increased levels of the protein.
The VMAT2-overexpressing mice exhibited a two-fold increase in vesicular transport, which increased dopamine release 84 percent. The mice also showed improved outcomes for anxiety and depressive behaviors, increased movement, and protection from the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP causes permanent symptoms of Parkinson’s disease and is used to study the disease in animal models. Overall, the work suggests that enhanced vesicular function can be sustained over time and thus interventions that target vesicular function might be beneficial to Parkinson’s disease as well as other disorders that involve storage and release of dopamine, serotonin, or norepinephrine neurotransmitters.
Citation: Lohr KM, Bernstein AI, Stout KA, Dunn AR, Lazo CR, Alter SP, Wang M, Li Y, Fan X, Hess EJ, Yi H, Vecchio LM, Goldstein DS, Guillot TS, Salahpour A, Miller GW. 2014. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc Natl Acad Sci U S A; doi: 10.1073/pnas.1402134111 [Online 16 June 2014].
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