Increasing Sonic Hedgehog Signaling Could Help Prevent PD Drug Side Effects

A new study led by researchers at the Graduate Center, CUNY, and the CUNY School of Medicine shows that drugs that increased signaling by a protein called sonic hedgehog, or Shh, can inhibit L-dopa induced dyskinesia, or LID, which causes involuntary movements in the limbs, face, and torso. The study appears in Communications Biology.

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

Shh has not previously been considered a neurotransmitter, but the new paper shows that it does in fact act as a neuromodulator. The researchers found that dopamine neurons use Shh to communicate with cholinergic neurons, which scientists have thought might play a role in LID. They then used animal models of Parkinson’s disease to show that decreased Shh signaling in the basal ganglia, caused by the death of dopamine neurons, facilitates LID. On the other hand, 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 therapeutics that act downstream in the Shh pathway in cholinergic neurons and begin clinical trials. “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 Andreas 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.”