EFFICACY OF GRAFTED IMMORTALIZED DOPAMINE NEURONS IN AN ANIMAL-MODEL OF PARKINSONISM - A REVIEW

Dopamine (DA) deficiency is one of the primary lesions in the pathogen esis of Parkinson disease (PD). Because of long-term toxicity of L-DOP A therapy, the grafting of fetal mesencephalic tissue containing dopam ine neurons or homogeneous populations of DA neurons into striatum app ears to be rational. Fetal tissue transplants have many problems which include legal (in some countries), ethical, paucity of tissue availab ility, heterogenicity of cell populations, and the presence of antigen -presenting cells that are responsible for rejection of allogeneic gra fts. In order to resolve the above problems, we have established immor talized 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 (1RB(3)AN(27)) was isolated, characterized, and tested in 6-hy droxydopamine (6-OHDA)-lesioned rats (a model of PD). These cells divi ded with a doubling time of about 26 h, expressed the LTa gene, and co ntained the tyrosine hydroxylase and dopamine transporter proteins and their respective mRNAs, which became elevated upon differentiation. T hese cells were nontumorigenic and nonimmunogenic and improved the sym ptoms 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 D A neurons generated in vitro by LTa gene insertion may be used in tran splant therapy without fear of tumor formation or rejection. (C) 1998 Academic Press.