Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathway for dopamine. Tyrosine hydroxylase (TH) catalyzes the synthesis of l-dopa, which must be converted to dopamine by aromatic l-amino acid decarboxylase (AADC). Since the endogenous AADC activity in the striatum is considered to be low, coexpression of both TH and AADC in the same striatal cells would increase the dopamine production and thereby augment the therapeutic effects. In the present study, the TH gene and also the AADC gene were simultaneously transduced into rat striatal cells, using two separate adeno-associated virus (AAV) vectors, AAV-TH and AAV-AADC. Immunostaining showed that TH and AADC were coexpressed efficiently in the same striatal cells in vitro and in vivo. Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01). These findings suggest an alternative strategy for gene therapy of PD and indicate that the simultaneous transduction with two AAV vectors can extend their utility for potential gene therapy applications.
Overview summary
In rodent models of Parkinson's disease (PD), the expression of tyrosine hydroxylase (TH), which catalyzes the synthesis of l-dopa, in the denervated striatum has been reported to induce behavioral recovery. l-Dopa is converted to dopamine by aromatic l-amino acid decarboxylase (AADC), but the endogenous AADC activity in the striatum is low. Therefore, both TH and AADC genes were cotransduced into rat striatal cells, using two separate adeno-associated virus (AAV) vectors, AAV-TH and AAV-AADC. More effective dopamine production, and more remarkable behavioral recovery, were observed in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with both vectors compared with rats treated with AAV-TH alone.
