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Cited by 67Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersParkinson's Disease Mechanisms and Treatments

Dopamine D2 Receptor Stimulation Potentiates PolyQ-Huntingtin-Induced Mouse Striatal Neuron Dysfunctions via Rho/ROCK-II Activation

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Deyts, Carole, Galan-Rodriguez, Beatriz, Martin, Elodie, Bouveyron, Nicolas, Roze, Emmanuel, Charvin, Delphine, Caboche, Jocelyne, Bétuing, Sandrine·2009·PLoS ONE
DOI 10.1371/journal.pone.0008287PMC PMC2790370
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Abstract

BACKGROUND: Huntington's disease (HD) is a polyglutamine-expanded related neurodegenerative disease. Despite the ubiquitous expression of expanded, polyQ-Huntingtin (ExpHtt) in the brain, striatal neurons present a higher susceptibility to the mutation. A commonly admitted hypothesis is that Dopaminergic inputs participate to this vulnerability. We previously showed that D2 receptor stimulation increased aggregate formation and neuronal death induced by ExpHtt in primary striatal neurons in culture, and chronic D2 antagonist treatment protects striatal dysfunctions induced by ExpHtt in a lentiviral-induced model system in vivo. The present work was designed to elucidate the signalling pathways involved, downstream D2 receptor (D2R) stimulation, in striatal vulnerability to ExpHtt. METHODOLOGY/PRINCIPAL FINDINGS: Using primary striatal neurons in culture, transfected with a tagged-GFP version of human exon 1 ExpHtt, and siRNAs against D2R or D1R, we confirm that DA potentiates neuronal dysfunctions via D2R but not D1R stimulation. We demonstrate that D2 agonist treatment induces neuritic retraction and growth cone collapse in Htt- and ExpHtt expressing neurons. We then tested a possible involvement of the Rho/ROCK signalling pathway, which plays a key role in the dynamic of the cytoskeleton, in these processes. The pharmacological inhibitors of ROCK (Y27632 and Hydroxyfasudil), as well as siRNAs against ROCK-II, reversed D2-related effects on neuritic retraction and growth cone collapse. We show a coupling between D2 receptor stimulation and Rho activation, as well as hyperphosphorylation of Cofilin, a downstream effector of ROCK-II pathway. Importantly, D2 agonist-mediated potentiation of aggregate formation and neuronal death induced by ExpHtt, was totally reversed by Y27632 and Hydroxyfasudil and ROCK-II siRNAs. CONCLUSIONS/SIGNIFICANCE: Our data provide the first demonstration that D2R-induced vulnerability in HD is critically linked to the activation of the Rho/ROCK signalling pathway. The inclusion of Rho/ROCK inhibitors could be an interesting therapeutic option aimed at forestalling the onset of the disease.

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  • Dopamine D2 receptor stimulation by dopamine acts in synergy with mutant Htt to increase aggregate formation, neuritic retraction, and striatal death through activation of the RhoA/ROCK/cofilin pathway, which can be reversed by ROCK inhibition.

    “Dopamine D2 receptor stimulation by dopamine has been found to act in synergy with mutant Htt to increase aggregate formation, neuritic retraction, and striatal death through activation of the RhoA/ROCK/cofilin pathway, which could be reversed by ROCK inhibition [201,209].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [201]

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Cited by

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Authors
Deyts, C., Galan-Rodriguez, B., Martin, E., Bouveyron, N., Roze, E., Charvin, D., Caboche, J., & Bétuing, S.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Bétuing, Sandrine
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-12-15
Volume
4
Issue
12
Pages
e8287
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0008287
PMC
PMC2790370
OpenAlex
W2056982361
Cited by
67
References
0
Citations by year
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FWCI
1.57
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Chicago (cc-by)
Funders
  • Cure Huntington's Disease Initiative
  • Centre National de la Recherche Scientifique
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
Huntington's disease, dopamine D2 receptor, striatal neurons, ROCK2, growth cone collapse, neuronal aggregation, neuronal cell death, dopamine D1 receptor, ROCK inhibitor, Y-27632, hydroxyfasudil
MeSH terms
Animals, Dopamine, Enzyme Activation, Humans, Neurons, Peptides, Neurites, Cell Death, Neostriatum, Receptors, Dopamine D1, Receptors, Dopamine D2, Quinpirole, Trinucleotide Repeat Expansion, Growth Cones, rho GTP-Binding Proteins, Protein Structure, Quaternary, RNA, Small Interfering, Serotonin Plasma Membrane Transport Proteins, Mice, rho-Associated Kinases

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