(10) NOVEL CELLULAR MODELS OF MITOCHONDRIAL NEUROLOGICAL DISEASE

G.A. Cortopassi¹, A. Wong¹, L. Cavelier¹, H. Collins², M.F. Seldin², M.L. Savontaus³ and M. McGrogan^4
1Dept. Molecular Biosciences, 1311 Haring Hall, University of California, Davis, CA 95616
²Rowe Program in Genetics, Departments of Biological Chemistry and Medicine, University of California, Davis, Davis, CA 95616
³Department of Medical Genetics, Institute of Biomedicine, University of Turku,  Finland 
⁴Layton Biosciences, Gilroy, CA

Mitochondrial genetic disease frequently affects neural cells.  However the pathogenetic  mechanism(s) of mitochondrial molecular disease have been mainly studied in non-neuronal cells, most frequently osteosarcoma cell lines.  In an attempt to generate a more relevant cellular model system for the study of the neuropathogenetic mechanisms in mitochondrial genetic disease, we have demonstrated the transfer of mutant mtDNAs from patient lymphoblasts to a pre-neuronal cell line N tera2 (Nt2).  Restriction digests were consistent with transfer of patient mtDNA, and homoplasmic lines were identified.  A potential issue was the contamination of transmitochondrial cell lines with patient nuclear DNA, but assay of >50 variable microsatellite loci was inconsistent with nuclear contamination by donor cells.  mtDNA and nuclear DNA copy number were similar in control and transmitochondrial cell lines.  Nt2 cells bearing mutant mitochondria were differentiable with retinoic acid into postmitotic cells with a neuronal morphology.  Such cells could represent a useful model in which to study the neuropathogenetic mechanism(s) of mtDNA mutations.

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