Abstract
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 diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID. We find that the pharmacological activation of Smoothened, a downstream effector of Shh, attenuates LID in the neurotoxic 6-OHDA- and genetic aphakia mouse models of Parkinson’s Disease. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from dopamine neurons or Smoothened activity in cholinergic interneurons promotes LID. Conversely, the selective expression of constitutively active Smoothened in cholinergic interneurons is sufficient to render the sensitized aphakia model of Parkinson’s Disease resistant to LID. Furthermore, acute depletion of Shh from dopamine neurons 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 therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa.
Highlights
L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson’s Disease
We present several lines of evidence indicating that the increase in DA signaling produced by L-Dopa acts in concert with reduced sonic hedgehog (Shh) signaling following dopamine neuron (DAN) degeneration to facilitate the formation and expression of LID: (1) in the 6-OHDA mouse, MPTP macaque, and AK−/− genetic mouse models of DAN loss, agonists of the Shh signaling effector Smo attenuate LID formation and expression (Fig. 8a); (2) conditional presynaptic ablation of Shh from DAN or postsynaptic Smo ablation from cholinergic interneuron (CIN) facilitate LID (Fig. 8b); (3) CINspecific expression of constitutively active Smo, SmoM2, blocks LID formation in the AK−/− mouse model of LID (Fig. 8c); (4) acute depletion of ShhDAN by prolonged optogenetic stimulation of DAN in otherwise intact mice results in LID-like abnormal involuntary movement (AIM) (Fig. 8d)
By identifying the commonality among these diverse paradigms which differ greatly in their etiology, we were able to pinpoint that the relative imbalance between Shh and DA signaling onto CIN is a critical facilitator of LID and a determinant of the severity of LID
Summary
L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson’s Disease. LID is a medication induced complication that emerges after repeated L-Dopa treatment of Parkinson’s disease patients with substantial DAN degeneration but does not present in untreated Parkinson’s disease or in treated healthy individuals[2,7,8] These observations suggest that DAN degeneration alters brain circuitry such that subsequent DA substitution therapy with L-Dopa is insufficient to fully normalize the functional pathology caused by DAN degeneration and instead promotes LID9. Recent work has demonstrated that treatment with L-Dopa alone is not sufficient to restore the normal properties of CIN in the Parkinson’s disease brain, as their disturbed activity and morphology remains or becomes further dysregulated following L-Dopa treatment[19,20] The complexity of these pathological alterations is highlighted by the fact that both suppressing and ablating CIN13,17,21, as well as optogenetic stimulation of CIN22 and pharmacological augmentation of cholinergic signaling, can attenuate LID in animal models[23]
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