Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models

Hum Cell. 2001 Mar;14(1):39-48.


This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Aromatic-L-Amino-Acid Decarboxylases / genetics
  • Disease Models, Animal
  • Dopamine / biosynthesis*
  • GTP Cyclohydrolase / genetics
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Transport Proteins*
  • Neuropeptides*
  • Parkinson Disease / genetics*
  • Parkinson Disease / therapy*
  • Rats
  • Tyrosine 3-Monooxygenase / genetics
  • Vesicular Biogenic Amine Transport Proteins
  • Vesicular Monoamine Transport Proteins


  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Neuropeptides
  • Vesicular Biogenic Amine Transport Proteins
  • Vesicular Monoamine Transport Proteins
  • Tyrosine 3-Monooxygenase
  • GTP Cyclohydrolase
  • Aromatic-L-Amino-Acid Decarboxylases
  • Dopamine