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Althoughl-DOPA is the drug of choice for Parkinson's disease, prolongedl-DOPA therapy results in decreased drug effectiveness and the appearance of motor complications. This may be due in part to the progressive loss of the enzyme, aromaticl-amino acid decarboxylase (AADC). We have developed an adeno-associated virus vector (AAV–hAADC) that contains human AADC cDNA under the control of the cytomegalovirus promoter. Infusion of this vector into the striatum of parkinsonian rats and monkeys improvesl-DOPA responsiveness by improving AADC-mediated conversion ofl-DOPA to dopamine. This is now the basis of a proposed therapy for advanced Parkinson's disease. A key concern has been that over-production of dopamine in striatal neurons could cause dopamine toxicity. To investigate this possibility in a controlled system, mixed striatal primary rat neuronal cultures were prepared. Exposure of cultures to high concentrations ofl-DOPA induced the following changes: cell death in nigral and striatal neurons, aggregation of neurofilaments and focal axonal swellings, abnormal expression of DARPP-32, and activation of astroglia and microglial cells. Transduction of cultures with AAV–hAADC resulted in efficient and sustained neuronal expression of the AADC protein and prevented all thel-DOPA-induced toxicities. The protective effects were due primarily to AADC-dependent conversion ofl-DOPA to dopamine and an increase in induction of vesicular monoamine transporter resulting in dopamine storage in cultured cells. These results suggest a neuroprotective role for AADC gene transfer againstl-DOPA toxicity. [ABSTRACT FROM AUTHOR]