Hedgehog Protein Stimulation Helps Parkinson's Patients

Drugs that increased signaling by a protein called sonic hedgehog, or Shh, can inhibit Levodopa induced dyskinesia, or LID, as per the study led by researchers at the Graduate Center, CUNY and the CUNY School of Medicine that appears in Communications Biology.

LID causes involuntary movements in the limbs, face, and torso. Deep brain stimulation can reduce LID, but the procedure is highly invasive and not all patients are eligible.

‘New drugs that downstream the Shh pathway in cholinergic neurons could help treat Parkinson's patients with less side effects.’
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“In rodent and non-human primate models, the administration of L-dopa together with sonic hedgehog agonists attenuate the expression of LID,” said Lauren Malave, Ph.D., first author and postdoctoral fellow at Columbia University, previously a Ph.D. student in the lab of Professor Andreas Kottmann, Ph.D., at the CUNY School of Medicine at City College of New York and the Graduate Center.

“We provide novel insight into the underlying mechanisms behind LID formation and provide a potential therapeutic solution.”

Parkinson’s disease is induced due to the death of dopamine neurons. Key to the new study, though, is that these neurons also produce neurotransmitters other than dopamine, including GABA, glutamate, and Shh.

Shh was not previously considered a neurotransmitter, but the new study shows that it does in fact act as a neuromodulator.

Dopamine neurons use Shh to communicate with cholinergic neurons, which scientists have thought might play a role in LID.

Researchers used animal models of Parkinson’s disease to show that decreased Shh signaling in the basal ganglia, caused by death of dopamine neurons, facilitates LID. Mimicking increased signaling by Shh reduced LID. Because of this, the authors suggest that the imbalance between dopamine and Shh after L-dopa treatment is a major cause of LID.

The next steps will be to develop new drugs that act downstream in the Shh pathway in cholinergic neurons and begin clinical trials.

Deep Brain Stimulation for Parkinson�s Disease
Deep brain stimulation using electrical impulses jumpstarts the nerve cells that produce the chemical messenger dopamine to reduce tremors and muscle rigidity that are the hallmark of Parkinson’s disease.

“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,” said Kottmann, who was the corresponding author on the paper.

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

This research was supported by the American Parkinson Disease Association and the National Institutes of Health and the Research Foundation of the City University of New York.

Source-Medindia