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Journal of Neuroscience, Vol 13, 5203-5211, Copyright © 1993 by Society for Neuroscience
Regulation of dopamine production by genetically modified primary fibroblasts
UJ Kang, LJ Fisher, TH Joh, KL O'Malley and FH Gage
Department of Neurosciences, University of California at San Diego, La Jolla 60638-0627.
Primary skin fibroblasts were genetically modified with catecholamine-
synthesizing enzyme genes and studied as potential syngeneic donor cells to
supply catecholamines in animal models of Parkinson's disease. Primary skin
fibroblasts obtained from inbred Fischer 344 rats were transduced with
tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC)
cDNAs using retroviral vector system. The transduced cells were
characterized in vitro by enzymatic assay, immunocytochemistry, and HPLC
analysis of catecholamine production and release. Accumulation of high
levels of dopamine was detected in the media in a time-dependent manner.
Secretion of dopamine and its metabolites appeared to be constitutive
without significant storage capacity in vesicles or regulation at the level
of secretion. The feasibility of regulating the final dopamine production
by the AADC- transduced cells was explored in two ways. First,
administration of various doses of the precursor, L-dopa, resulted in a
controlled production of dopamine by these cells. Second, coculturing AADC-
transduced cells with TH-transduced cells in various proportions allowed
control of dopamine production. TH-transduced cells served as an endogenous
source of precursor. We propose the use of these cells to study the role of
AADC in restoring the dopamine-deficient behavior and to compare the effect
of dopamine-producing cells with L-dopa-producing cells either by
cografting TH-transduced cells with AADC-transduced cells or by grafting
TH-transduced cells alone. The role of AADC in vivo will be assessed in
future experiments involving animal models of Parkinson's disease.
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