STUDIES ON THE MECHANISM OF EARLY-ONSET MACULAR DEGENERATION IN CYNOMOLGUS MONKEYS .2. SUPPRESSION OF METALLOTHIONEIN SYNTHESIS IN THE RETINA IN OXIDATIVE STRESS

Initial investigations done in this laboratory detected increased albu min and decreased glyceraldehyde 3-phosphate dehydrogenase concentrati ons in the retina of an animal model manifesting early onset macular d egeneration. Both glyceraldehyde 3-phosphate dehydrogenase and albumin are markers of oxidative stress in cells. In this study, we used the same animal model to study further biochemical and physiological proce sses which may be involved in the pathogenesis of early onset macular degeneration in monkeys. We detected 60% lower catalase and glutathion e peroxidase activities in the affected retinas suggesting lower antio xidant activities and oxidative stress. One of the consequences of oxi dative stress is the production of metallothionein. a low molecular we ight protein also induced by high concentrations of heavy metals such as zinc. Metallothionein was detected by RT-PCR in these monkey retina s. However initial quantitative PCR studies on this protein showed tha t the synthesis of metallothionein in affected retinas appears to be l ess than in normal controls. The affected retinas also showed a fourfo ld lower zinc concentration compared with the normal controls. No sign ificant difference, however, could be detected in the zinc concentrati ons in plasma samples. Since induction of metallothionein synthesis is mediated by transcription factors which require heavy metals such as zinc for binding to specific sites in the DNA. the lowered zinc concen tration may, thus, correlate with the lowered metallothionein expressi on. And since metallothionein is suggested to function as a free radic al scavenger, the lowered metallothionein synthesis may consequently c ontribute to increased peroxidation reactions in the affected retinas. It appears therefore, that oxidative stress and the decreased metallo thionein synthesis may be involved in the pathogenesis of early onset macular degeneration in this animal model. (C) 1996 Academic Press Lim ited