Gene therapy strategy may ease Parkinson’s disease dyskinesia

Levodopa, a standard treatment for Parkinson’s disease, can cause uncontrolled movements called dyskinesia — and this side effect may be driven by changes in a specific receptor component in certain brain cells, a new study shows.

Scientists found that an experimental gene therapy strategy aimed at decreasing levels of this receptor component in those specific brain cells could blunt dyskinesia’s development and substantially ease established dyskinesia in a mouse model.

“This is a way that we might be able to control dyskinesia with a completely novel strategy,” D. James Surmeier, PhD, senior author of the study at Northwestern University, said in a university news story. “Nearly 80 percent of Parkinson’s disease patients will develop dyskinesia. At present, we have a very limited set of tools to help these patients right now. This work points to the possibility of a non-invasive gene therapy that would be transformative.”

The study, “Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia,” was published in Neuron.

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Levodopa treatment can trigger dyskinesia

Parkinson’s is a neurological disorder marked by the degeneration and death of brain cells that make dopamine, a signaling molecule that’s key for coordinating movements. Low dopamine levels ultimately drive Parkinson’s symptoms.

Levodopa and its derivatives primarily work by being converted into dopamine in the brain. These medications have for decades been a gold standard of Parkinson’s treatment, and they can be highly effective for easing disease symptoms — but as with any medical treatment, levodopa can cause side effects. In particular, many people who take levodopa long term develop dyskinesia, defined by jerky, uncontrollable movements.

Although it’s well-established that levodopa can trigger dyskinesia, the precise molecular mechanisms by which this drug causes this side effect have been obscure.

Working in a mouse model, researchers found that repeated levodopa treatment that induced dyskinesia led to molecular abnormalities in a subset of brain cells called indirect pathway spiny projection neurons, or iSPNs. Under normal circumstances, these nerve cells are thought to help the brain prevent unwanted movements.

The researchers specifically found that dyskinesia was linked to increased levels of N-methyl-D-aspartate (NMDA) receptors containing a specific subunit called GluN2B in iSPNs. NMDA receptors normally help nerve cells communicate with each other, but changes in these receptors can disrupt nerve-to-nerve communication.

“Connections between neurons dictate when they become active and how they perform their duties in controlling movement. In late-stage [Parkinson’s] patients, levodopa begins to ‘scramble’ these connections, which we think leads to uncontrolled movement or dyskinesia,” Surmeier said. “When we induce dyskinesia, we see this change in NMDA receptors in this subset of striatal neurons thought to be responsible for suppression of unwanted movement.”

Reducing GluN2B eased dyskinesia in mice

Spurred by this finding, the researchers tested the effects of an experimental gene therapy strategy designed to decrease levels of the GluN2B subunit of NMDA receptors in iSPNs. They found that this treatment could substantially lessen established dyskinesia and blunt dyskinesia’s development when given before repeated levodopa treatment in the mouse model.

“What was very exciting was that – in contrast to almost everything else that has been tried in the last 30 years – knocking down this one NMDA receptor subunit in this particular group of cells reversed established dyskinesia,” Surmeier said.

Notably, knocking down this receptor subunit did not make levodopa any less effective at controlling Parkinson’s symptoms.

“[K]nocking down … the GluN2B subunit specifically in iSPNs attenuated the induction and expression of [levodopa-induced dyskinesia] without compromising the symptomatic benefit of levodopa,” the researchers concluded.

Although further work to test the safety and efficacy of this approach is needed, the researchers said their gene therapy “raises the possibility of an alternative strategy for not just preventing [levodopa-induced dyskinesia] but also reversing established [levodopa-induced dyskinesia].”