brain gene transfer. METHODS: AAV-XIAP or AAV-green fluorescent protein (GFP) (control) were first tested in cultured SY5Y cells for protection against toxicity from models of PD (proteasome inhibition, -synuclein) or HD (mutant Q111 huntington). AAV-XIAP or AAV-GFP were then injected into the substantia nigra (SNc) of normal rats given the systemic proteasome inhibitor PSI, which recapitulates many features of human PD. Transgenic mice expressing a mutant huntington exon 1 also received bilateral striatal injections of AAV-XIAP or AAV-GFP. RESULTS: In culture, PSI, -synuclein, and Q111 all caused 45–60% cell loss, which was completely blocked by AAV-XIAP. In the rat PSI model, a 50–60% loss of SNc dopaminergic neurons was observed in control animals, yet again, AAV-XIAP caused 100% neuronal protection. Transgenic HD mice showed a reduction in baseline motor behavior by rotorod testing compared with matched littermates. Although unaffected by AAV-GFP, AAV-XIAP caused an improvement in rotorod testing, and by 1 month after treatment, these mice reach levels of normal mice. This effect was sustained for 3 months, which was the entire lifespan of these animals. There was a corresponding increased survival in AAV-XIAP HD mice compared with controls. CONCLUSION: AAV-XIAP seems to be a very effective agent for neuroprotection in a newly described rat model of PD, and in transgenic HD mice, it reverses baseline motor deficits and improves survival. With the interest in neuroprotection in PD, the lack of effective therapy for HD, and our recent demonstration that AAV gene therapy can be safe in human PD, these strategies may hold therapeutic promise.