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Solving the Mystery of Parkinson's

Anthony West, PhD, associate professor and vice chair of the Department of Neuroscience, stands at the beginning of the drug pipeline for Parkinson’s disease (PD), a chronic and progressive movement disorder caused by the death of dopamine neurons in the brain. PD is diagnosed in about 50,000 people in the United States each year, according to the National Institutes of Health.

Dr. West’s basic science research contributes to the foundation for discovery of improved medications to treat PD. That can’t come soon enough considering the rate of the disease increases with age, and no means of prevention has been discovered.

His latest work is aimed at reversing, potentially, some of the damage PD inflicts on the brain.

PD was first diagnosed 200 years ago by a London doctor who wrote about the “shaking palsy.” While the gold-standard treatment, L-dopa, was first administered in the 1960s, it has been found to lose efficacy over time. Newer drugs are also helping to control the symptoms and severity of the disease. But there is no cure.

Dr. West has been studying dopamine since graduate school, trying to understand its effect on striatal circuits, neural pathways that mediate motor, cognitive and behavioral functions. He and other researchers are now searching for non-dopaminergic targets.

“The problem is that the dopamine system tries to regulate itself homeostatically,” he said. “The brain upregulates or downregulates dopamine receptor proteins, which mediate the effects of the transmitter on neuron function, and it loses synapses [the contact points where one neuron communicates with another]. If you give a drug, it isn’t really acting like a natural transmitter because you’ve lost synaptic contacts. So it works for a little while, but the side effects kick in. The patient keeps losing dopamine cells. There’s no therapy that stops the progression of the disease so that’s obviously another hot research area.”

Dr. West is working with existing neurotransmitters, like nitric oxide (NO), a signaling molecule that can spread easily into cells and act on nearby neurons, even if they’re not connected by a synapse. NO has been linked to the injury and death of neurons and consequent neurodegenerative disorders. In animal models of PD, the NO signaling pathway does not appear to be properly activated.

He’s working with Kuei Y. Tseng, MD, PhD, associate professor of cellular and molecular pharmacology, to develop and test potential therapeutics that can slow the progression of PD by normalizing the function of pathways activated by NO. They’ve used phosphodiesterase inhibitors, typically used for erectile dysfunction, to treat Huntington’s disease (HD), which Dr. West also studies, an inherited disorder that, like PD, results in the death of brain cells.

“Drugs that inhibit phosphodiesterases actually work quite well for reversing the synaptic pathology in HD by augmenting signaling pathways downstream of nitric oxide, whereas drugs that do the opposite and actually inhibit the pathway seem to work really well for PD,” Dr. West said. “We’re identifying targets that are not lost in the disease process. We’re hoping that this will lead to symptomatic improvements and the drug seems to do that. But we’re also looking for potential disease-modifying improvements that may reverse some of the synaptic pathology that’s occurring after the dopamine neurons die off.”

“We think that drugs that act to decrease nitric oxide signaling might actually do that because when we stop treating after seven days, we still see lasting improvements three days later,” Dr. West said. “There is still improvement even after the drug has left the system. That suggests there’s some kind of modification going on in the circuit as a result of the chronic drug treatment program.”

Other researchers in the field have tapped into other neurotransmitters, but Dr. West and his team are among the few going after intracellular signal cascades that are overactive in PD.

“It’s downstream of dopamine so we’re not worrying about fixing the dopamine,” he said. “We’re showing that you can target something that’s modulated by dopamine and restore that signaling pathway. We’re showing that you can restore biochemical, electrophysiological and behavioral measures of the disease by targeting a relatively novel pathway.”

Dr. West’s study of neurons and chemical reactions, his struggle to understand the mystery of PD, will continue to shed light on the disease, spark new ideas and inform the creation of new therapeutics that can treat, but also protect and restore.

“Maybe the drugs we’re using aren’t really the answer right now,” said the neuroscientist, who mentions that his aunt has lived with Parkinson’s for 15 years. “We suspect they will have off-target effects in other brain regions. But I’m excited that we now understand how the system should work. As better tools come along we should be able to selectively reverse the pathology in these particular neurons. With better tools, we can go after one of the nodes that malfunctions in PD and maybe come up with some really good selective therapies that don’t have side effects like the current therapies. That’s exciting.”

This article first appeared in the Summer 2017 edition of Helix Magazine.

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