LID is a side effect of dopamine replacement therapy, leading to involuntary movements in the limbs, face and torso of Parkinson's patients.
"The work provides a strong rationale for exploring the Shh signaling pathway in the adult brain to identify existing drugs and novel drug targets for developing effective anti-LID therapies without cancer-inducing liability," Dr. Andreas Kottman of the CUNY School of Medicine at City College of New York and the Graduate Center in New York City told Reuters Health by email.
As reported in Communications Biology, Dr. Kottman and colleagues found that diminished Shh signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID.
They also determined that activation of Smoothened - a downstream effector of Shh - using a Smoothened agonist, attenuates LID in both mouse and macaque models of Parkinson's.
By contrast, they found that reducing Shh secretion from dopamine neurons or decreasing Smoothened activity in cholinergic interneurons promotes LID.
Further, acute depletion of Shh from dopamine neurons in mice in the absence of L-Dopa produces LID-like involuntary movements.
The authors conclude, "These findings indicate that augmenting Shh signaling in the L-Dopa-treated brain may be a promising therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa."
Dr. Kottman noted, "Potent Smoothened agonists exist; however, their cancer-inducing potential raises concerns about their long-term use. Careful toxicology and risk/benefit analyses have to be conducted first."
"The next steps," he said, "will be to identify existing or new agonists to downstream effectors that have no cancer-inducing potential."
Dr. Alberto Espay, Director and Endowed Chair, Gardner Family Center for Parkinson's disease and Movement Disorders at the University of Cincinnati Academic Health Center, called the study "intriguing preclinical work" that could open "a novel avenue of investigation into LID."
That said, he noted, "The relevance of these findings will require demonstrating that the modulatory mechanism is also at play in humans affected with Parkinson's."
Further, he said, "Parkinson's is not one disease, despite its name. Hence, it is unclear who among those with PD these mice models of LID might reflect."
"If Shh signaling is critical in humans, an Shh bioassay to select those in the vast biological universe of Parkinson's disease most likely to develop Shh-related LID will be needed," he said. "Only such an assay could identify those in whom therapeutic Shh modulation might be considered as an antidyskinetic approach."
SOURCE: https://go.nature.com/3uFLktL Communications Biology, online September 22, 2021.
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