New Neuromodulator for Drug-induced Movement Disorder in Parkinson's Identified

Parkinson's patients may be aided by sonic hedgehog protein pathway stimulation as per a study “Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson’s disease and L-Dopa induced dyskinesia”, at The Graduate Center, CUNY, and the CUNY School of Medicine, published in the journal Communications Biology.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects movement due to loss of nerve cells – neurons that produce a chemical messenger (neurotransmitter) in the brain called dopamine (black substance).

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‘Movement disorders like L-dopa-induced dyskinesia (LID as a side effect of dopamine therapy) in Parkinson's patients may be aided by sonic hedgehog protein pathway stimulation. The study found a new neuromodulator – ‘Shh’ to be involved in driving this LID. ’

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PD is characterized by the formation of inclusion proteins called Lewy bodies, triggered by the misfolding of a protein called alpha-synuclein that accumulates in a part of the brain called the substantia nigra.

Drug-Induced Dyskinesia

Dopamine replacement therapy (a type of Parkinson's treatment that induces Levodopa, or L-dopa) may result in involuntary movements in the limbs, face, and torso after a few years as side effect called L-dopa induced dyskinesia (LID).

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Existing treatments like deep brain stimulation can alleviate LID. However, the procedure is highly invasive that hinders the eligibility of many patients. Hence, study team looked for an alternative approach through sonic hedgehog protein pathway stimulation.

It was found that drugs that increased signaling by a protein called sonic hedgehog, or Shh, can inhibit LID. This potentially helps most Parkinson’s patients from the debilitating side effects.

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The New Neuromodulator

‘Shh’ has not previously been considered a neurotransmitter (chemical messenger of the brain). The present study reveals that it does in fact act as a neuromodulator. It was found that dopamine neurons use Shh to communicate with cholinergic neurons (that plays a significant role in LID).

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The result was validated using the animal models of Parkinson’s disease. It was proved that decreased Shh signaling in the basal ganglia, caused by the death of dopamine neurons, facilitates LID. In addition, increased signaling by Shh reduced LID.

“In rodent and non-human primate models, the administration of L-dopa together with sonic hedgehog agonists attenuates the expression of LID. We provide novel insight into the underlying mechanisms behind LID formation and provide a potential therapeutic solution,” says Lauren Malave, Ph.D., first author, and postdoctoral fellow at Columbia University, previously a Ph.D. student.

The study thereby suggests that the imbalance between dopamine and Shh after L-dopa treatment is a major cause of LID. The team is set to develop new therapeutics that act downstream in the Shh pathway in cholinergic neurons and begin clinical trials.

Source-Medindia