Comparative analysis of neurodegenerative markers in ten different animal models for retinal degeneration reveals prevalence of non-apoptotic cell death mechanisms

Abstract

Purpose: Photoreceptor cell death in inherited retinal degeneration is often seen as a process governed by apoptosis. However, an increasing body of evidence suggests the activity of alternative cell death mechanisms. Since this issue is of major importance for the development of therapies for retinal degeneration, we set out to study markers for apoptotic and non-apoptotic cell death in ten different animal models for inherited retinal degeneration. These included human homologous models for autosomal dominant (P23H and S334ter transgenic rats) and autosomal recessive Retinitis Pigmentosa (rd1, rd2, rd10, Cngb1 KO, Rho KO mice), Leber’s Congenital Amaurosis (Rpe65 KO), and achromatopsia (cpfl1, Cnga3 KO mice).

Methods: We studied in situ a number of metabolic markers for apoptosis (BAX expression, cytochrome c leakage, activities of caspase-9 and -3), non-apoptotic cell death (activities of histone deacetylase [HDAC], poly-ADP-ribose-polymerase [PARP], calpain) and cGMP.

Results: We found that markers for non-apoptotic cell death (activation of calpain, HDAC and PARP as well as accumulation of PAR) were increased during photoreceptor degeneration in all analyzed animal models, along with cGMP (except in Rpe65 KO). On the other hand, except for the S334ter rat, all the studied animal models shared a remarkable scarcity or absence of markers for apoptosis (BAX upregulation and translocation into mitochondria, cytochrome c leakage and activation of caspases-9 and -3).

Conclusions: Our work conclusively demonstrates the importance of non-apoptotic mechanisms in inherited retinal degeneration and has clear ramifications for potential therapeutic approaches. For most mutations, anti-apoptotic strategies are likely to be less successful compared to approaches targeting cGMP signaling, epigenetic processes and calpain activity, which appear far more promising.

Keywords: 695 retinal degenerations: cell biology • 648 photoreceptors • 696 retinal degenerations: hereditary