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

Autor: Santiago Uribe-Cano, Andreas H. Kottmann, Lev Starikov, Dustin R Zuelke, Lauren Malave, Heike Rebholz, Chuan Qin, Erwan Bezard, Eitan Friedman, Qin Li
Přispěvatelé: Columbia University [New York], City University of New York [New York] (CUNY), Graduate Center of the City University [New York, NY, USA], Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), GHU Paris Psychiatrie et Neurosciences, Danube Private University [Krems, Autriche] (DPU), China Academy of Medical Sciences [Beijing, China] (Institute of Laboratory Animal Sciences), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Motac Neuroscience Ltd [Manchester, UK], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Martinez Rico, Clara
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Parkinson's disease
genetic structures
Dopamine
Medicine (miscellaneous)
Levodopa
Mice
0302 clinical medicine
Biology (General)
Sonic hedgehog
0303 health sciences
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
Dopaminergic
Parkinson Disease
3. Good health
embryonic structures
Basal ganglia
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
medicine.symptom
General Agricultural and Biological Sciences
medicine.drug
animal structures
QH301-705.5
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
medicine
Animals
Hedgehog Proteins
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
030304 developmental biology
Dyskinesias
business.industry
medicine.disease
Abnormal involuntary movement
eye diseases
Disease Models
Animal
Dyskinesia
biology.protein
Cholinergic
sense organs
Smoothened
business
Neuroscience
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Communications Biology
Communications Biology, Nature Publishing Group, 2021, 4 (1071), ⟨10.1038/s42003-021-02567-3⟩
Communications Biology, Vol 4, Iss 1, Pp 1-16 (2021)
Communications Biology, 2021, 4 (1071), ⟨10.1038/s42003-021-02567-3⟩
ISSN: 2399-3642
DOI: 10.1038/s42003-021-02567-3⟩
Popis: 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.
Lauren Malave et al. examine the impact of sonic hedgehog signaling in the dorsal striatum in L-Dopa induced dyskinesia (LID) animal models. Their results suggest that increasing sonic hedgehog signaling can reduce the severity of LID and abnormal involuntary movements, suggesting future therapeutic approaches to mitigate dyskinetic comorbidities of long-term treatment with L-Dopa.
Databáze: OpenAIRE
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