Role of inhibitors of apoptosis (IAPs) in retinal ganglion cell death and dendrite remodelling.

Abstract

Neuronal viability and connectivity is essential for neuronal function in heath and disease. The aim of this study was to elucidate factors and mechanisms that govern the maintenance and remodelling of RGC dendrites, as well as neuronal cell death in ageing and neurodegenerative diseases. Using PCR technique, the expression pattern of caspases 3,6-9 and inhibitors of apoptosis (lAPs), namely neuronal IAP (NIAP), cellular IAP1 and 2 (clAP1 and 2), X-chromosome linked IAP (XIAP), Survivin, Bruce and Livin was determined in young adult (6 weeks), mature (24-52 weeks), old (88 weeks) and diseased retinae of Wistar albino and Brown Norway (BN) rats. Caspase expression was not altered during maturation and ageing in both strains. In ageing Wistar, NIAP, clAP2 and XIAP and clAP1 were decreased in 88 compared to 24-52 weeks, while Survivin, Bruce and Livin were slightly increased with age. lAPs expression was generally decreased in mature (24- 52 weeks) BN retinae compared to younger (6 weeks). Furthermore, validation of the expression of these molecules at protein level was carried out using western blotting and immunofluorescence techniques. clAP1 protein levels were downregulated in RGCL of BN rats. Reduction of clAP1 did not alter caspase activity but led to impairment in the survival pathway. Older BN retinae demonstrated compromised RGC morphology, but there was no retinal cell loss. Microbead experimental glaucoma model demonstrated no alteration in caspase expression upon induction of glaucoma. NIAP, clAP2, Survivin and Livin were up-regulated, while Bruce was down-regulated in glaucomatous eyes. clAP1 and XIAP expression remain similar between control and experimental eye. In conclusion, reduction in lAPs, which may lead to impairment in survival pathways might be the underlaying cause of reduction in dendrite complexity. Compromised RGC morphology makes a preparatory platform for neurodegenerative process observed in glaucoma disease where age is a major risk factor