Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration

Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which t his mutation induces HD remains unknown, although alterations in protein de gradation are involved, To study intrinsic cellular mechanisms involved, To study Intrinsic to the mutation, we examined dissociated postnatally deriv ed cultures of striatal neurons from transgenic mice expressing exon 1 of t he human HD gene carrying a CAG repeat expansion. While there was no differ ence in cell death between wild-type and mutant littermate-derived cultures , the mutant striatal neurons exhibited elevated cell death following a sin gle exposure to a neurotoxic concentration of dopamine, The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes, The autophag ic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this ca se by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.