Stimulation of Sonic Hedgehog Protein Pathway May Benefit Parkinson’s Patients

According to a study published in Communications Biology by researchers at the Graduate Center, CUNY, and the CUNY School of Medicine, drugs that increase signaling by a protein called sonic hedgehog, or Shh, can inhibit Levodopa-induced dyskinesia, or LID. Involuntary movements of the limbs, face, and torso are caused by LID. Deep brain stimulation can reduce LID, but it is a highly invasive procedure for which not all patients are candidates.

Levodopa, also known as L-dopa, is widely regarded as the most effective Parkinson’s disease treatment available today. However, after a few years of treatment, almost all patients experience a debilitating side effect known as L-dopa induced dyskinesia, or LID, which causes involuntary movements in the limbs, face, and torso. Deep brain stimulation can help with LID, but it is a highly invasive procedure for which not all patients are candidates.

Levodopa (or L-dopa) is the gold standard for treating Parkinson’s disease worldwide. However, long-term use causes side effects such as involuntary body movements. This is referred to as levodopa-induced dyskinesia (LID).

Drugs that increase the signaling of Sonic Hedgehog (Shh) can help suppress the involuntary movements associated with dopamine replacement therapy for those with Parkinson’s disease.

A new study led by researchers at the Graduate Center, CUNY, and the CUNY School of Medicine demonstrates that drugs that increase signaling by a protein known as sonic hedgehog, or Shh, can inhibit LID. According to the authors, such a treatment has the potential to help the vast majority of Parkinson’s patients.

The findings were published in the journal Communications Biology.

“In rodent and non-human primate models, the administration of L-dopa in conjunction with sonic hedgehog agonists attenuates the expression of LID,” said Lauren Malave, Ph.D., first author and postdoctoral fellow at Columbia University, who was previously a Ph.D. student in Professor Andreas Kottmann’s lab at City College of New York and the Graduate Center.

“We provide novel insight into the underlying mechanisms underlying LID formation, as well as a potential therapeutic solution.”

Sonic Hedgehog Protein Pathway Stimulation Could Help Parkinson’s Patients

Deep brain stimulation is an invasive procedure that can be used to treat LID. This option, however, is time-consuming, and not everyone is eligible for the procedure. A new study in rodents and nonhuman primates suggests that drugs that boost the signaling of a protein called sonic hedgehog may be able to mitigate the effects of LID. The findings may open up previously unavailable treatment options for some people living with Parkinson’s disease.

Parkinson’s disease is caused by the death of dopamine neurons, which is why the disease is treated with medications that, once in the body, are converted to dopamine. The new study, however, focuses on the fact that these neurons also produce neurotransmitters other than dopamine, such as GABA, glutamate, and Shh.

Shh was not previously thought to be a neurotransmitter, but the new study shows that it does act as a neuromodulator. The researchers discovered that dopamine neurons communicate with cholinergic neurons via Shh, which scientists thought might play a role in LID.

They then used Parkinson’s disease animal models to show that decreased Shh signaling in the basal ganglia, caused by dopamine neuron death, facilitates LID. Shh, on the other hand, reduced LID by mimicking increased signaling. As a result, the authors propose that the imbalance between dopamine and Shh following L-dopa treatment is a major cause of LID. The next step will be to create new therapeutics that act downstream in the Shh pathway in cholinergic neurons, followed by clinical trials.

“Deep brain stimulation does not help everyone; it is very invasive, and not everyone is a candidate for the surgery. The procedure is also not available to everyone,” said Kottmann, the paper’s corresponding author. “What we discovered in this study is that these dyskinesias can be greatly suppressed in several animal models by replacing not only dopamine but dopamine combined with agonists that mimic the effects of sonic hedgehog.”

The American Parkinson Disease Association, the National Institutes of Health, and the City University of New York Research Foundation all contributed to this study. The researchers’ hypothesis was based on the protein sonic hedgehog (Shh). This is a chemical signal that is important for brain and spinal cord development, as well as motor skill learning.

First, they hypothesized that Shh is essential for motor skill learning and that decreased expression of Shh due to dopamine neuron degeneration facilitates the formation and expression of LID. The researchers then used animal models to see if a synergistic relationship between L-dopa and Shh agonists could reverse the formation and appearance of LID. They investigated this using three different Parkinson’s disease models.