Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice

Abstract

Purpose Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS). This study aims to generate a homozygous global Cep250 knockout (KO) mouse and study the resulting phenotype. Methods We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration. Long-term follow-up studies using optical coherence tomography (OCT) and electroretinography (ERG) were performed. Results OCT and ERG results demonstrated gradual thinning of the outer nuclear layer (ONL) and progressive attenuation of the scotopic ERG responses in Cep250 −/− mice. More TUNEL signal was observed in the ONL of these mice. Immunostaining of selected OS proteins revealed mislocalization of these proteins in the ONL of Cep250 −/− mice. Interestingly, untargeted metabolomics analysis revealed arginine-related metabolic pathways were altered and enriched in Cep250 −/− mice. Mis-localization of a key protein in the arginine metabolism pathway, arginase 1 (ARG1), in the ONL of KO mice further supports this model. Moreover, adeno-associated virus (AAV)-based retinal knockdown of Arg1 led to similar architectural and functional alterations in wild-type retinas. Conclusions Altogether, these results suggest that dysregulated arginine metabolism contributes to retinal degeneration in Cep250 −/− mice. Our findings provide novel insights that increase understanding of retinal degeneration in ciliopathy disorders.

A Review for Artificial Intelligence Based Protein Subcellular Localization

“…Most cellular biological processes, such as the nucleocytosolic shuttling of transcription factors [3], the relocalization of mitochondrial proteins during apoptosis [4], and the endocytic uptake of cell-surface cargo receptors, all rely on precise protein localization. Conversely, mislocalization is often associated with cellular dysfunction and diseases, such as cancer [5,6], neurodegenerative diseases [7,8], and metabolic disorders [9,10].…”