Unraveling a role for dopamine in Huntington's disease: the dual role of reactive oxygen species and D2 receptor stimulation.
Huntington's disease (HD), an inherited neurodegenerative disorder, results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation leads to protein aggregation and neurotoxicity. Despite its widespread expression in the brain and body, mutated huntingtin causes selective degeneration of striatal projection neurons. In the present study, we investigate the role of dopamine (DA) in this preferential vulnerability. Using primary cultures of striatal neurons transiently expressing GFP-tagged-exon 1 of mutated huntingtin, we show that low doses of DA (100 microM) act synergistically with mutated huntingtin to activate the proapoptotic transcription factor c-Jun. Surprisingly, DA also increases aggregate formation of mutated huntingtin in all cellular compartments, including neurites, soma, and nuclei. DA-dependent potentiation of c-Jun activation was reversed by ascorbate, a reactive oxygen species (ROS) scavenger, and SP-600125, a selective inhibitor of the c-Jun N-terminal kinase (JNK) pathway. By contrast, DA effects on aggregate formation were reversed by a selective D2 receptor antagonist and reproduced by a D2 agonist. Similarly, striatal neurons from D2 knockout mice showed no effect of DA on aggregate formation. Blocking ROS production, JNK activation, or D2 receptor stimulation significantly reversed DA aggravation of mutated huntingtin-induced striatal death. The combined treatment with the ROS scavenger and D2 antagonist totally reversed DA's effects on mutated huntingtin-induced striatal death. Thus, the present results provide insights into the cellular mechanisms that govern striatal vulnerability in HD and strongly support a dual role of JNK activation and D2 receptor signaling in this process.
Charvin
Delphine
D
Unité Mixte de Recherche 7102, Signalisation Neuronale et Régulations Géniques, 9 Quai Saint Bernard, 75005 Paris, France.
Vanhoutte
Peter
P
Pagès
Christiane
C
Borrelli
Emilliana
E
Borelli
Emiliana
E
Caboche
Jocelyne
J
D000704:Analysis of Variance; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000873:Anthracenes; D065127:Dopamine D2 Receptor Antagonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C432165:pyrazolanthrone; D004298:Dopamine