Exploring the combined role of genetic and non-genetic factors for developing Age-Related Macular Degeneration: A systems level analysis of disease subgroups, risk factors, and pathways

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Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins

Publication . Valdés-Sánchez, Lourdes; Calado, Sofia; de la Cerda, Berta; Aramburu, Ana; García-Delgado, Ana B; Massalini, Simone; Montero-Sánchez, Adoración; Bhatia, Vaibhav; Rodríguez-Bocanegra, Eduardo; Diez-Lloret, Andrea; Rodríguez-Martínez, Daniel; Chakarova, Christina; Bhattacharya, Shom S; Díaz-Corrales, Francisco J

Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.

2019-12-31Journal article

Open access