Efficacy of Grafted Immortalized Dopamine Neurons in an Animal Model of Parkinsonism: A Review

• Published in: Molecular Genetics and Metabolism Vol. 65; no. 1; pp. 1 - 9
• Main Authors: Prasad, Kedar N., Clarkson, Edward D., La Rosa, Francisco G., Edwards-Prasad, Judith, Freed, Curt R.
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.1998
• Subjects: 6-hydroxydopamine lesion; Animals; Cell Line, Transformed; Disease Models, Animal; Dopamine - biosynthesis; dopamine neurons; Fetal Tissue Transplantation; immortalization; Neurons - metabolism; Neurons - transplantation; Parkinson disease; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Rats; SV40 large T-antigen gene; transplantation; Parkinson disease; SV40 large T-antigen gene; dopamine neurons; 6-hydroxydopamine lesion; immortalization; transplantation
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1006/mgme.1998.2726

Dopamine (DA) deficiency is one of the primary lesions in the pathogenesis of Parkinson disease (PD). Because of long-term toxicity ofl-DOPA therapy, the grafting of fetal mesencephalic tissue containing dopamine neurons or homogeneous populations of DA neurons into striatum appears to be rational. Fetal tissue transplants have many problems which include legal (in some countries), ethical, paucity of tissue availability, heterogenicity of cell populations, and the presence of antigen-presenting cells that are responsible for rejection of allogeneic grafts. In order to resolve the above problems, we have established immortalized DA neurons from fetal rat mesencephalon by inserting the large T-antigen (LTa) gene of the SV40 virus into the cells. A clone of DA neurons (1RB3AN27) was isolated, characterized, and tested in 6-hydroxydopamine (6-OHDA)-lesioned rats (a model of PD). These cells divided with a doubling time of about 26 h, expressed the LTa gene, and contained the tyrosine hydroxylase and dopamine transporter proteins and their respective mRNAs, which became elevated upon differentiation. These cells were nontumorigenic and nonimmunogenic and improved the symptoms of neurological deficits (methamphetamine-induced rotation) in 6-OHDA-lesioned rats. The differentiated DA neurons were more effective than undifferentiated ones. These studies suggest that immortalized DA neurons generatedin vitroby LTa gene insertion may be used in transplant therapy without fear of tumor formation or rejection.