Targeted Gene Therapy Boosts Levodopa’s Benefits in Mouse Study

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An image of mitochondria, a component of cells that supply the cell's with energy and are essential to cellular health.

A gene therapy targeting the substantia nigra, the brain region with dopamine-producing nerve cells, may boost the benefits of levodopa for people with Parkinson’s disease, a study reports.

This idea was tested in a new mouse disease model — one in which Parkinson’s symptoms appeared after disrupting a protein complex in mitochondria, organelles involved in the production of energy in cells (the cell’s powerplants). The gene therapy appeared to restore healthy movement to these mice.

And the model suggested, reportedly for a first time, that damage to mitochondria in the substantia nigra can lead to the loss of dopamine-producing nerve cells.

The study, “Disruption of mitochondrial complex I induces progressive parkinsonism,” was published in Nature.

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Levodopa is considered the most effective treatment for Parkinson’s. Over time, however, response to levodopa can wear off, meaning its effects diminish before it is time for the next dose. Wearing off tends to happen more frequently as the disease progresses to more advanced stages, causing fluctuations of motor symptoms.

A team of researchers in the U.S. and Spain found that delivery of a virus containing the genetic instructions for making AADC — a protein that converts levodopa to dopamine — could help to increase levodopa’s effectiveness. The virus was delivered specifically to the substantia nigra of mice that modeled some of the key features of neurodegeneration seen in people with Parkinson’s, including a loss in dopamine release.

By returning to nerve cells in the substantia nigra the ability to convert levodopa into dopamine, the mice regained the ability to move swiftly across an open field.

Notably, these observations made the researchers challenge the long-held idea that the loss of dopamine release in the target structure of substantia nigra’s dopamine-producing nerve cells — a brain region called the dorsal striatum — is enough to produce the motor symptoms of Parkinson’s.

Rather, it appears that damage to the mitochondria of dopamine-producing nerve cells in the substantia nigra itself is enough to trigger a sequence of events that reflect what happens in the human disease.

Mitochondrial protein complex “dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm,” the researchers wrote.

When these mitochondria are no longer able to work properly, the ability of neurons to function correctly in the brain is affected, and without a sufficient source of energy, neurons eventually die.

“The development of effective therapies to slow or stop Parkinson’s disease progression requires scientists know what causes it,” James Surmeier, PhD, the study’s lead author, and chair of neuroscience at Northwestern University’s Feinberg School of Medicine, said in a university press release.

“This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurons is enough to cause a human-like parkinsonism in a mouse,” Surmeier added.

“Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons,” he said.

This new model also allows scientists to study changes in the brain starting with mitochondrial disruption, before a progressive loss of dopamine-releasing neurons leads to motor symptoms, and so help to identify people at risk of Parkinson’s.

“This new ‘human-like’ model may help us develop tests that would identify people who are on their way to being diagnosed with Parkinson’s disease in five or 10 years,” Surmeier said. “Doing so would allow us to get them started early on therapies that could alter disease progression.”

The work was supported by the Michael J. Fox Foundation, the JPB Foundation, the IDP Foundation, the Flanagan Foundation and a grant from the National Institutes of Health.