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 form aggregates and to produce a selective degeneration of striatal neurons, despite a ubiquitous expression of mutated huntingtin. The aim of this work was to explore the role of dopamine in this striatal vulnerability. We first set up an experimental model, using transient transfection in primary cultures of striatal neurons. We showed in that model an activation of 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 and showed i) a potentiation, via reactive oxygen species (ROS), of JNK/cJun activation induced by mutated huntingtin ; ii) an increase of aggregate formation via D2 receptor stimulation, 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 D2 antagonist treatment in a rat model of HD. Rats were infected into the striatum with lentivirus expressing either normal or mutated huntingtin. An early treatment with haloperidol decanoate showed a protection against both aggregate formation and striatal dysfunction (Charvin et al., soumis). Our results highlight a key role of dopamine in striatal neurons vulnerability in HD, and offer new therapeutic strategies for the treatment of HD.
Dopamine and striatal neurodegeneration in Huntington's disease : towards the identification of new therapeutic targets.