The drug target VMAT2 has appeared in biomedical news lately because of a pair of FDA approvals. One medicine treats the iatrogenic movement disorder tardive dyskinesia, the first approved to do so, and the other is for symptoms of Huntington’s disease.
When Emory folks see VMAT2, they should think of two things: the neurotransmitter dopamine, and Parkinson’s research conducted by Gary Miller and his colleagues. They have made a case that activators of VMAT2 would be beneficial in Parkinson’s, but the drugs in the news were inhibitors, and presumably would make Parkinson’s worse.
VMAT2 (vesicular monoamine transporter 2) is responsible for transporting dopamine into synaptic vesicles, tiny packages for delivery. As Miller’s lab has shown, mice deficient in VMAT2 can be a model for the non-motor and motor aspects of Parkinson’s. In these mice, not only are certain nervous system functions impaired, but the dopamine packaging problem inflicts damage on the neurons.
Miller’s more recent work on a related molecule called SV2C is puzzling, but intriguing. The gene encoding SV2C had attracted attention because of its connection to the striking ability of cigarette smoking to reduce Parkinson’s risk, possibly mediated by nicotine’s effect on dopamine in the brain.
I say puzzling because SV2C’s role in brain cells can’t be described as easily as VMAT2’s. Miller and colleagues generated mice lacking SV2C and the result is less dopamine in the brain and mild motor deficits, but “the mechanism underlying this observed reduction in dopamine content and release is unclear.” SV2C could be doing several things related to dopamine and synaptic vesicles, the scientists write.
Still, the evidence that SV2C has a special role in Parkinson’s is piling up. When brains from people who had died of Parkinsons, Alzheimer’s, and other neurodegenerative diseases were examined, SV2C levels were altered only in the Parkinson’s patients’ brains.
The Miller lab also showed that SV2C has a connection to the protein alpha-synuclein, a major constituent of Lewy bodies, the protein clumps that are the pathological hallmark of Parkinson’s. In addition, SV2C’s cousin SV2A is the target of the antiepileptic drug levetiracetam, and that provides more support for pursuing SV2C.