Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson’s disease and L-Dopa induced dyskinesia

• DOI: 10.1038/s42003-021-02567-3
• Publication Date: 2021-09-22T10:03:10Z
• Authors: Lauren Malave; Dustin R. Zuelke; Santiago Uribe-Cano; Lev Starikov; Heike Rebholz; Eitan Friedman; Chuan Qin; Qin Li; Erwan Bezard; Andreas H. Kottmann
• Keywords: Smoothened

Abstract L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson’s Disease. The mechanistic underpinnings LID remain obscure. Here we report that diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by degeneration midbrain neurons facilitates formation and expression LID. We find pharmacological activation Smoothened, downstream effector Shh, attenuates neurotoxic 6-OHDA- genetic aphakia mouse models Employing conditional loss-of-function approaches, show reducing Shh secretion from or Smoothened activity cholinergic interneurons promotes Conversely, selective constitutively active sufficient to render sensitized model Disease resistant Furthermore, acute depletion through prolonged optogenetic stimulation otherwise intact mice absence produces LID-like involuntary movements. These findings indicate augmenting treated brain may be promising therapeutic approach mitigating dyskinetic effects long-term treatment with L-Dopa.