Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

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 alfa-sheddase ADAM10, seems to be upregulated in human retinas affected by retinitis pigmentosa, a genetic disease leading to photoreceptor 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 Rpe65Leu450Leu 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 disease pathogenesis.