PT  - JOURNAL ARTICLE
AU  - Lauren Malave
AU  - Dustin R. Zuelke
AU  - Santiago Uribe-Cano
AU  - Lev Starikov
AU  - Heike Rebholz
AU  - Eitan Friedman
AU  - Chuan Qin
AU  - Qin Li
AU  - Erwan Bezard
AU  - Andreas H. Kottmann
TI  - Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Abnormal Involuntary Movements
AID  - 10.1101/2020.03.09.983759
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.09.983759
4099  - http://biorxiv.org/content/early/2020/10/15/2020.03.09.983759.short
4100  - http://biorxiv.org/content/early/2020/10/15/2020.03.09.983759.full
AB  - L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson’s Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminshed sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons (DANs) facilitates the formation and expression of LID. We demonstrate that augmenting Shh signaling with agonists of the Shh effector Smoothened attenuates LID in mouse and macaque models of PD. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from DANs or Smo activity in cholinergic interneurons (CINs) promotes LID. Conversely, the selective expression of constitutively active Smo (SmoM2) in CINs is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, acute depletion of Shh from DANs through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising and unexpected novel therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-DopaCompeting Interest StatementThe authors have declared no competing interest.