Study Explores Imbalances in Brain That Lead to LID

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by Marisa Wexler |

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An imbalance between the signaling molecules dopamine and sonic hedgehog in the brain may be the cause of the movement disorder caused by dopamine-replacing medicines used to treat Parkinson’s disease.

That’s according to findings published in Communications Biology, in the study, “Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson’s disease and L-Dopa induced dyskinesia.”

Parkinson’s disease is caused by the death and dysfunction of dopaminergic neurons — nerve cells that make a signaling molecule called dopamine. The gold standard treatment for Parkinson’s is levodopa and its derivatives, which basically work by giving the brain more raw material with which to make dopamine.

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While these medicines can effectively alleviate symptoms of Parkinson’s, their long-term use almost always leads to a side effect called L-dopa induced dyskinesia, or LID, which is characterized by uncontrolled movements of the limbs, face, and torso. A surgical treatment called deep brain stimulation can alleviate this side effect, but it has numerous drawbacks.

“Deep brain stimulation doesn’t help everyone, it’s very invasive, and not all people are eligible for the surgery. The procedure is also not accessible to everyone,” Andreas Kottmann, PhD, a professor at the CUNY School of Medicine at City College of New York and study co-author, said in a press release.

The biological mechanisms that cause LID to develop are poorly understood, which has made it difficult to design treatments to alleviate LID.

Now, an international team of researchers has shown that LID likely develops because of an imbalance of signaling molecules in the brain.

While dopaminergic neurons primarily signal to other cells using dopamine, these cells also make other signaling molecules — including a protein called sonic hedgehog (Shh). Named for the video game character, Shh is known to regulate a variety of processes during development, but its functions in the adult brain are not well understood.

In multiple rodent and non-human primate models, the researchers demonstrated that increasing Shh activity reduced the extent of LID.

Further experiments indicated that the Shh released by dopaminergic neurons was acting on another class of nerve cell in the brain, called cholinergic interneurons (CINs). Using genetic engineering, the researchers created mice with CINs that were unable to respond to Shh, and other mice whose CINs had elevated Shh signaling. Results showed increased LID when Shh signaling was lessened, whereas increased Shh signaling eased LID.

Other experiments demonstrated that reducing the amount of Shh released by dopaminergic neurons led to LID-like symptoms. The amount of Shh needed to alleviate LID also was dependent on the amount of dopamine-replacing medicines used to induce LID.

Considering all these findings together, the researchers concluded that, under normal conditions, CINs are receiving signals from dopaminergic neurons via both dopamine and Shh. In Parkinson’s disease, where these neurons are dysfunctional, both molecular signals decrease.

Then, when a person with Parkinson’s initiates treatment with a dopamine-replacing therapy, their CINs start receiving high amounts of dopamine signaling — but they are still receiving low signaling with Shh. This imbalance in signals likely drives the development of the dyskinesia, according to the scientists.

“What we find in this study is that in several animal models, by replacing not only dopamine but dopamine together with agonists [compounds that activate cellular receptors] that mimic the effects of sonic hedgehog, these dyskinesias can be very much suppressed,” Kottmann said.

The team said this finding “provides a strong rationale” for using medications that mimic Shh activity to combat LID, which may be a promising avenue for future research.