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Volume 16, Number 14, Issue of July 15, 1996 pp. 4449-4456
Copyright ©1996 Society for Neuroscience

Double Transduction with GTP Cyclohydrolase I and Tyrosine Hydroxylase Is Necessary for Spontaneous Synthesis of L-DOPA by Primary Fibroblasts

Received Dec. 13, 1995; revised March 26, 1996; accepted April 17, 1996.

Craig Bencsics¹, Stephen R. Wachtel¹, Sheldon Milstien², Kazuyuki Hatakeyama³, Jill B. Becker⁴, and Un Jung Kang¹

¹ Departments of Neurology, Pharmacological and Physiological Sciences, and Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637, ² Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland 20892-4096, ³ Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and ⁴ Department of Biopsychology, University of Michigan, Ann Arbor, Michigan 48104

Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson's disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH₄), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH₄ to support TH activity. To determine the role of BH₄ in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase I, an enzyme critical for BH₄ synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH₄ and 3,4-dihydroxy-L-phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo microdialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibroblasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo. These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH₄ is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH₄.

Key words: tetrahydrobiopterin; Parkinson's disease; gene therapy; retrovirus vector; transplantation; catecholamine

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