Role of Aromatic l‐Amino Acid Decarboxylase for Dopamine Replacement by Genetically Modified Fibroblasts in a Rat Model of Parkinson's Disease

• Published in: Journal of neurochemistry Vol. 69; no. 5; pp. 2055 - 2063
• Main Authors: Wachtel, Stephen R., Bencsics, Craig, Kang, Un Jung
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.11.1997; Blackwell
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Animals; Aromatic-L-Amino-Acid Decarboxylases - biosynthesis; Aromatic-L-Amino-Acid Decarboxylases - genetics; Biological and medical sciences; Catecholamines - metabolism; Cell Transplantation - methods; Corpus Striatum - cytology; Corpus Striatum - metabolism; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Denervation; Disease Models, Animal; Dopamine; Dopamine - biosynthesis; Dopamine - metabolism; Female; Fibroblasts - transplantation; Genetic Therapy - methods; GTP Cyclohydrolase - biosynthesis; GTP Cyclohydrolase - genetics; GTP cyclohydrolase I; Homovanillic Acid - metabolism; Levodopa - metabolism; l‐DOPA; Medical sciences; Microdialysis; Neurology; Parkinson Disease - enzymology; Parkinson Disease - therapy; Rats; Rats, Inbred F344; Recombinant Proteins - biosynthesis; Striatum; Transfection; Tyrosine 3-Monooxygenase - biosynthesis; Tyrosine 3-Monooxygenase - genetics; Tyrosine hydroxylase; Animal model; Rat; Central nervous system; Parkinson disease; Lyases; Tyrosine 3-monooxygenase; Carboxy-lyases; Degenerative disease; Levodopa; Nervous system diseases; Dopamine; Enzyme; Rodentia; Basal ganglion; Corpus striatum; Catecholamine; In vitro; Cerebral disorder; Carbon-carbon lyases; Vertebrata; Mammalia; Central nervous system disease; Neurotransmitter; Aromatic-L-amino-acid decarboxylase; Oxidoreductases; Gene therapy; Brain (vertebrata); Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1997.69052055.x

: Investigations of gene therapy for Parkinson's disease have focused primarily on strategies that replace tyrosine hydroxylase. In the present study, the role of aromatic l‐amino acid decarboxylase in gene therapy with tyrosine hydroxylase was examined by adding the gene for aromatic l‐amino acid decarboxylase to our paradigm using primary fibroblasts transduced with both tyrosine hydroxylase and GTP cyclohydrolase I. We compared catecholamine synthesis in vitro in cultures of cells with tyrosine hydroxylase and aromatic l‐amino acid decarboxylase together versus cocultures of cells containing these enzymes separately. l‐DOPA and dopamine levels were higher in the cocultures that separated the enzymes. To determine the role of aromatic l‐amino acid decarboxylase in vivo, cells containing tyrosine hydroxylase and GTP cyclohydrolase I were grafted alone or in combination with cells containing aromatic l‐amino acid decarboxylase into the 6‐hydroxydopamine‐denervated rat striatum. Grafts containing aromatic l‐amino acid decarboxylase produced less l‐DOPA and dopamine as monitored by microdialysis. These findings indicate that not only is there sufficient aromatic l‐amino acid decarboxylase near striatal grafts producing l‐DOPA, but also the close proximity of the enzyme to tyrosine hydroxylase is detrimental for optimal dopamine production. This is most likely due to feedback inhibition of tyrosine hydroxylase by dopamine.