# Mechanisms of Inhibition of L-Dopa Induced Dyskinesia (LID) by GPCR Smoothened Activation.

> **NIH NIH R21** · CITY COLLEGE OF NEW YORK · 2020 · $235,500

## Abstract

Dopamine (DA) substitution therapy by L-DOPA effectively ameliorates many Parkinson's Disease (PD)
symptoms caused by DA neuron (DAN) degeneration but leads to the formation of debilitating L-DOPA
induced dyskinesia (LID) in most patients after several years of treatment. This treatment complication
severely curtails the therapeutic window of L-DOPA and finding strategies that overcome LID formation
remains a pressing clinical need. We recently found that DAN not only release dopamine but also the secreted
cell signaling factor Sonic Hedgehog (Shh) which they use to signal selectively to cholinergic (CIN) and fast
spiking (FS) interneurons among all dopaminergic targets. CIN have become implicated in LID independently
via multiple lines of research and clinical observations. Thus our findings suggested that LID might emerge
because CIN and FS are exposed to high DA but low Shh signaling during DA replacement therapy.
Consistent with this hypothesis we found that stimulation of the Shh pathway through agonists of the Shh
effector GPCR Smoothened (Smo) in addition to L-DOPA attenuates LID in mouse- and non-human primate-models of PD. While our primate studies suggest that augmenting Shh/Smo signaling together with L-DOPA
might attenuate LID in PD it is unlikely that agonists of Smo are viable drugs in humans because of their
severe oncogenic liability. Instead we aim to identify druggable events downstream of Shh/Smo signaling in
CIN and FS in in vivo models of PD and LID. The hope is that emerging targets might be more selective and
their pharmacological manipulation more tolerable than stimulating Smo signaling. To enable this goal we
propose here to adapt and validate methods that allow (1) optic control over Shh/Smo signaling in the basal
ganglia (BG) of LID expressing animals and (2) neuron subtype specific metabolic tagging and identification of
proteins and their post-translational modifications in response to Smo activation in LID.
In aim1 we will produce chimeric Melanopsin:Smoothened proteins (Mel:Smo) and determine their light
sensitivity in vitro. Light responsive Mel:Smo chimeras will then be expressed in vivo in a Cre dependent
manner from Adeno-Associated Viruses (AAV) in CIN of the dorso-lateral striatum of the LID sensitive Aphakia
mouse line. We will test whether light activation of Mel:Smo chimeras attenuates LID and will quantify that
effect relative to Smo agonists that activate non recombinant Smo. These reagents will test the hypothesis that
Smo signaling in CIN causes LID attenuation. In aim2 we will identify proteins that become modified in
response to Smo signaling selectively in either CIN or FS interneurons of mice that were acutely injected with
either agonists or antagonists of Smo. This approach is enabled by mice expressing Cre in CIN or FS
interneurons and that carry a conditional methionyl-tRNA synthetase L274G point mutation (MetRS) allele
which causes the incorporation of azidonorleucine instead of methionine int...

## Key facts

- **NIH application ID:** 9876786
- **Project number:** 1R21AG065682-01
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** Andreas H Kottmann
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2020-09-09 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876786

## Citation

> US National Institutes of Health, RePORTER application 9876786, Mechanisms of Inhibition of L-Dopa Induced Dyskinesia (LID) by GPCR Smoothened Activation. (1R21AG065682-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9876786. Licensed CC0.

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