Identification of a Common Non-Apoptotic Cell Death Mechanism in Hereditary Retinal Degeneration

Abstract

Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

Organotypic retinal explant cultures as in vitro alternative for diabetic retinopathy studies

“…The percentage of cleaved caspase-3 positive cells was about 6-fold lower than the total number of TUNEL-positive cells, indicating that cell death via apoptosis was activated only in a minor fraction of dying cells. A variety of other, non-apoptotic mechanisms have been proposed to contribute to retinal cell death (Arango-Gonzalez et al, 2014), including autophagy and parthanatos (Punzo et al, 2009;Feenstra et al, 2013;Arango-Gonzalez et al, 2014). Future studies should reveal which cell death pathways different from apoptosis are triggered in diabetic conditions and which of the many cell types in the inner retina are mainly affected by these.…”

Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene

“…17 Apart from the physiologic importance in phototransduction, PDE and cGMP are likely also involved in pathologic events, since high cGMP levels, and subsequent photoreceptor cell death, are encountered in several animal RP models based on mutations of PDE6, and interestingly also as a consequence of mutations in apparently unrelated genes. [18][19][20][21] The PDE6 enzyme is composed of two catalytic subunits called a (A) and b (B) and two identical inhibitory c subunits. 22 Approximately 3% to 4% of arRP cases 21,23 are caused by mutations in the PDE6A gene, coding for the a subunit and resulting in a defective PDE6 enzyme or no enzyme at all.…”

Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal Degeneration

“…The latter animals demonstrated significant upregulation of Csp-3/7 activity as compared to wt, supporting a previously proposed hypothesis for the involvement of apoptosis in the mechanism of photoreceptor cell death 26,27 in addition to nonapoptotic pathways. 21 We found that the level of active Csp-3/7 in T17M Csp-12 À/À retinas was not statistically different from that found in wt and Csp-12 À/À retinas using one-way ANOVA. However, a t-test demonstrated a 50% increase in cleaved Csp-3/7 in T17M Csp-12 À/À retinas as compared to wt (P ¼ 0.026).…”

“…4) since they are the major calpain forms expressed in retinas and because of their well-documented pathological roles in necrotic photoreceptor cell death. 21 Results from this experiment revealed that while the total l-and m-calpain activity in T17M retinas increased by 3-fold as compared to wt, T17M Csp-12 À/À retinas demonstrated a 2-fold decrease in the level of total calpain activity as compared to T17M retinas. This decrease was not statistically different when compared to wt.…”

“…[18][19][20][21] Indeed, an increase in the levels of intracellular Ca 2þ , regardless of whether this is a physiological or pathological event, activates a number of enzymes directly, or indirectly via Ca 2þ -binding proteins. We analyzed the activity of l-calpain and m-calpain in P30 T17M Csp-12 À/À retinas (Fig.…”