Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Abstract

Background: Genetic and age-related photoreceptor degeneration impairs vision in millions of individuals worldwide, often enhanced by factors that modify the genotype-phenotype correlation, independently of the primary cause of the disease. Secreted Frizzled Related Protein 1 (SFRP1), a modulator of Wnt signalling and of the enzymatic activity of the αsheddase ADAM10, seems to be upregulated in human retinas affected by retinitis pigmentosa, a genetic disease leading to photoreceptors' degeneration. Here we have asked whether SFRP1 contributes to photoreceptor degeneration.Methods: Adult mice deficient in the Sfrp1 gene were used to address the implication of SFRP1 in maintaining retinal homeostasis in normal and photo-damaged conditions. Molecular and morphological preservation of the retinas was evaluated by western blot as well as histological, in situ hybridisation and immunohistochemical analysis using confocal and transmission electron microscopy. Visual function was assessed by electroretinography.Results: In Sfrp1 null mice, the outer limiting membrane (OLM) was discontinuous and the photoreceptors were disorganized and more prone to light-induced damage, significantly enhancing the effect of the Rpe65 Leu450Leu genetic variant -present in the mouse genetic background-which confers sensitivity to light-induced stress. These alterations worsened with age and led to a significant decrease in visual function. These defects were associated to an increased proteolysis of Protocadherin 21 (PCDH21), an adhesion molecule localized to the inner portion of the photoreceptor outer segment, and N-cadherin, a component of the OLM.Conclusions: SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in light of the initial observation that SFRP1 expression is upregulated in cases of retinitis pigmentosa and of the evidence that elevated levels of SFRP1 contribute to Alzheimer´s disease pathogenesis.

Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions

“…CDHR1 forms physical connections between nascent, evaginating OS discs and the periciliary ridge of the IS of rod and cone photoreceptors. The characterisation of genes that regulate expression of retinal cadherins are candidate genes for unsolved cases of retinal degeneration; ADAM10 and SFRP1 may regulate cleavage of the CDHR1 ectodomain (Cisneros et al, 2020) necessary to uncouple mature OS discs from the IS throughout life, although confirmation is required. The identification of the IS binding partner of CDHR1 may provide an additional candidate gene for retinal degeneration and provide important information to further unravel the molecular basis of OS disc morphogenesis (Goldberg et al, 2016).…”

“…ADAM10 cleaves the ectodomains of a number of cadherins and protocadherins, and is co-expressed with a number of retinal cadherins in the developing chicken retina (Yan et al, 2011). An increased proportion of cleaved, C-terminal CDHR1 fragments were identified in Sfrp1 -/-(Secreted Frizzled Related Protein 1) mice when compared to wildtype and rd10 mice (Cisneros et al, 2020). As SFRP1 can act as a negative regulator of ADAM10 (Esteve et al, 2011), this suggests that CDHR1 could be a substrate for ADAM10.…”

“…It was recently suggested that ADAM10 (disintegrin and metalloproteinase family member 10), an alpha-secretase enzyme that forms part of the ADAM family that have known roles in cell partitioning during development, may be a candidate for the enzyme responsible for the cleavage of the CDHR1 ectodomain (Cisneros et al, 2020). ADAM10 cleaves the ectodomains of a number of cadherins and protocadherins, and is co-expressed with a number of retinal cadherins in the developing chicken retina (Yan et al, 2011).…”

“…The mapping of degenerative pathways may suggest therapeutic opportunities for intervention. Moreover, they may suggest other candidate genes for retinal degeneration (such as ADAM10, and its regulators such as SFRP1) (Cisneros et al, 2020). Sfrp1 -/mice have been shown to have disorganised OS which is thought in part due to increased proteolysis of CDHR1 through potentiation of the activity of ADAM10 (Cisneros et al, 2020).…”

“…Moreover, they may suggest other candidate genes for retinal degeneration (such as ADAM10, and its regulators such as SFRP1) (Cisneros et al, 2020). Sfrp1 -/mice have been shown to have disorganised OS which is thought in part due to increased proteolysis of CDHR1 through potentiation of the activity of ADAM10 (Cisneros et al, 2020). Further work is required to confirm these interactions, which if confirmed, may present the possibility of digenic inheritance in unsolved cases of retinal degeneration (as identified similarly with ROM1 and PRPH2).…”