Abstract
Calcium (Ca2+ ) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+ -dependent calpain proteases, generating spatiotemporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatiotemporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor, although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggest a causal link between Ca2+ dysregulation and primary, nonapoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.
Highlights
The primary light-detecting cells in the retina are rod and cone photoreceptors
The rd1 and rd10 lines carry different mutations in the Pde6b gene, 236 whereas the cpfl1 line suffers from a mutation in the homologous, cone-specific Pde6c gene
Our data suggests that peaks for calpain activity, calpain-2, and transferase dUTP nick end labelling (TUNEL) are correlated in space and time starting in the centre of the retina before spreading to the periphery following the onset of degeneration
Summary
The primary light-detecting cells in the retina are rod and cone photoreceptors (rods and cones). Cones are responsible for day time vision, while rods are responsible for vision under dim light conditions. Rods and/or cones degenerate and die in a heterogeneous group of genetic diseases called hereditary retinal degeneration (RD). The most common disease within this group is Retinitis Pigmentosa (RP), which first causes the loss of rods, followed by secondary cone loss. One in 3,500 individuals is affected by RP (Bertelsen et al, 2014), which presents in humans as a progressive loss of night vision, gradual constriction of the visual field (“tunnel vision”), and eventually complete blindness (Hartong et al, 2006). A related retinal dystrophy is achromatopsia, affecting about one in 30,000 individuals (Remmer et al, 2015), in which typically only the cones are lost
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