Abstract
The asparaginase and isoaspartyl peptidase 1 (ASRGL1) is an L-asparaginase and beta-aspartyl peptidase enzyme that may be involved in the formation of L-aspartate, a neurotransmitter that can operate as an excitatory neurotransmitter in some brain regions. Although variants in ASRGL1 have been reported in retinitis pigmentosa (RP) patients, the in vivo functions and mechanisms of ASRGL in RP remains unknown due to the lack of suitable disease models. To explore the role of ASRGL in RP, we generated an Asrgl1 knockout mouse model (Asrgl1 KO) using the CRISPR/Cas9 technique. Asrgl1 ablation in mice led to an attenuated electroretinogram (ERG) response around 8 months. The thickness of the outer nuclei layer (ONL) started to decrease around 9 months in Asrgl1 KO mice and gradually intensified at 12 and 15 months. Immunostaining revealed thinner inner segment (IS) and thinner outer segment (OS) as well as the progressive degeneration of rod and cone cells in Asrgl1 KO mice. One hundred forty-nine transcriptional differentially expressed genes (DEGs) were found by RNA-seq in Asrgl1 KO retina. These DEGs were linked to a number of biological processes that were considerably enriched, including gastrointestinal disease and organismal injury and abnormalities. By analysis of canonical pathways, glucocorticoid receptor signaling was the most significant canonical pathway altered in Asrgl1 KO retina. Several molecules, including NFE2L2, IL-4, Foxp3, and Fos, were in the central nodes of the interaction network in Asrgl1 KO retina. In summary, our study provided a knockout mouse model for a better understanding of the molecular mechanism for ASRGL1-related RP.
Highlights
Retinitis pigmentosa is one of the most common causes of visual impairment around the world, including symptoms such as night blindness and progressive loss of peripheral vision in the early stage, and no complete yet effective treatment exists up to date (Ferrari et al, 2011)
We generated a novel Asrgl1 knockout mouse model to investigate the in vivo roles of ASRGL1, a new retinitis pigmentosa (RP) gene reported in 2016
We found Asrgl1 ablation led to an attenuated ERG response around 8 months
Summary
Retinitis pigmentosa is one of the most common causes of visual impairment around the world, including symptoms such as night blindness and progressive loss of peripheral vision in the early stage, and no complete yet effective treatment exists up to date (Ferrari et al, 2011). The prevalence of this disorder is approximately 1:4,000 (Hartong et al, 2006). Over 90 genes have been associated with nonsyndromic RP according to the RetNet database Only about 50%–60% of RP cases can be explained by these mutations, and the pathological and molecular mechanisms of some of the genes remain unknown (Daiger et al, 2013; Huang et al, 2015)
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