TY - JOUR T1 - Vesicular Monoamine Transporter-2 and Aromatic<span class="sc">l</span>-Amino Acid Decarboxylase Enhance Dopamine Delivery after<span class="sc">l</span>-3,4-Dihydroxyphenylalanine Administration in Parkinsonian Rats JF - The Journal of Neuroscience JO - J. Neurosci. SP - 3266 LP - 3274 DO - 10.1523/JNEUROSCI.19-08-03266.1999 VL - 19 IS - 8 AU - Won Yong Lee AU - Jin Woo Chang AU - Nicole L. Nemeth AU - Un Jung Kang Y1 - 1999/04/15 UR - http://www.jneurosci.org/content/19/8/3266.abstract N2 - Medical therapy in Parkinson’s disease (PD) is limited by the short-duration response and development of dyskinesia that result from chronic l-3,4-dihydroxyphenylalanine (l-DOPA) therapy. These problems occur partly because the loss of dopamine storage sites leads to erratic dopamine delivery. Vesicular monoamine transporter-2 (VMAT-2) plays a critical role in dopamine storage by packaging dopamine into synaptic vesicles and regulating sustained release of dopamine. To restore the capacity to produce and store dopamine in parkinsonian rats, primary skin fibroblast cells (PF) were genetically modified with aromatic l-amino acid decarboxylase (AADC) and VMAT-2 genes. After incubation withl-DOPA in culture, the doubly transduced fibroblast cells (PFVMAA) produced and stored dopamine at a much higher level than the cells with either gene alone. PFVMAA cells in culture released dopamine gradually in a constitutive manner. Genetically modified fibroblast cells were grafted in parkinsonian rat striata, and l-DOPA was systemically administered. Higher dopamine levels were sustained for a longer duration in rats grafted with PFVMAA cells than in those grafted with either control cells or cells with AADC alone. These findings underscore the importance of dopamine storage capacity in determining the efficacy of l-DOPA therapy and illustrate a novel method of gene therapy combined with precursor administration to overcome the major obstacles of PD treatment. ER -