Huntington's disease (HD) is caused by a polyglutamine expansion in the huntingtin protein.This mutation confers new properties on this protein, including the ability to formaggregates and to produce a selective degeneration of striatal neurons, despite a ubiquitousexpression of mutated huntingtin. The aim of this work was to explore the role of dopaminein this striatal vulnerability. We first set up an experimental model, using transienttransfection in primary cultures of striatal neurons. We showed in that model an activationof the pro-apoptotic JNK/cJun pathway by mutated huntingtin (Garcia, Charvin and Caboche,2004). In a second step, we combined treatments with low doses of dopamine andshowed i) a potentiation, via reactive oxygen species (ROS), of JNK/cJun activation inducedby mutated huntingtin ; ii) an increase of aggregate formation via D2 receptorstimulation, iii) an amplification of neuronal toxicity via these two combined effects. Thus,our data strongly support that dopamine is involved in striatal neuron vulnerability in HD(Charvin et al., 2005). Then, we have evaluated in vivo, the therapeutic effects of a D2antagonist treatment in a rat model of HD. Rats were infected into the striatum with lentivirusexpressing either normal or mutated huntingtin. An early treatment with haloperidoldecanoate showed a protection against both aggregate formation and striatal dysfunction(Charvin et al., soumis). Our results highlight a key role of dopamine in striatal neuronsvulnerability in HD, and offer new therapeutic strategies for the treatment of HD.
