ASRGL1, also known as asparaginase-like-1 protein, is an L-asparaginase and beta-aspartyl peptidase enzyme. It catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia, and cleaves isoaspartates, which can impact protein folding and proteolysis [1,2,4,6]. This enzyme may be involved in the formation of L-aspartate, an excitatory neurotransmitter in some brain regions [3].

In ALS, RNA sequencing, immunohistochemistry, and western blotting showed diminished ASRGL1 expression in brain samples. Loss of ASRGL1 led to TDP-43 aggregation in the cytoplasm, as TDP-43 is a substrate for ASRGL1. ASRGL1 silencing in cultured neurons and female mouse motor cortex triggered misfolded, fragmented, phosphorylated, and mislocalized TDP-43, while its overexpression restored neuronal viability. Overexpression of HML-2, harbored within the ASRGL1 gene, led to ASRGL1 silencing [1].

In hepatocellular carcinoma (HCC), ASRGL1 expression was higher in patients than in adjacent normal tissue, and its knockdown in HepG2 and Li-7 cell lines inhibited cell proliferation, migration, invasion, and promoted apoptosis both in vitro and in vivo. Bioinformatics and flow cytometry analysis indicated ASRGL1 might regulate the cell cycle, and its blockade promoted P53 protein expression and reduced cyclin B and CDK1 proteins expression [2].

In Asrgl1 knockout mouse models, ablation led to attenuated electroretinogram response around 8 months, decreased outer nuclei layer thickness from 9 months, and progressive degeneration of rod and cone cells. RNA-seq found 149 transcriptional differentially expressed genes linked to biological processes like gastrointestinal disease and organismal injury [3]. A mouse model with c.578_579insAGAAA mutation in Asrgl1 showed significant and progressive decrease in scotopic and photopic electroretinographic responses at early ages, loss of cone outer segments, and decrease in the expression of relevant markers [5]. A zebrafish model overexpressing mutant hASRGL1 developed retinal abnormalities and loss of cone photoreceptors [6].

In conclusion, ASRGL1 plays essential roles in multiple biological processes. Its function in protein folding and proteolysis through isoaspartate cleavage, and in neurotransmitter formation is significant. ASRGL1 knockout mouse models have revealed its crucial roles in diseases such as ALS, HCC, and retinal degeneration, contributing to a better understanding of the molecular mechanisms underlying these diseases.

References:

1. Garcia-Montojo, Marta, Fathi, Saeed, Rastegar, Cyrus, Steiner, Joseph, Nath, Avindra. 2024. TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression. In Nature communications, 15, 4163. doi:10.1038/s41467-024-48488-7. https://pubmed.ncbi.nlm.nih.gov/38755145/

2. Wang, Xudan, Wang, Yang, Yang, Long, Wang, Jianlin, Tao, Kaishan. 2022. ASRGL1 downregulation suppresses hepatocellular carcinoma tumorigenesis in a CDK1-dependent manner. In Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 55, 955-966. doi:10.1016/j.dld.2022.12.003. https://pubmed.ncbi.nlm.nih.gov/36572570/

3. Zhou, Yu, Tian, Wanli, Jiang, Xiaoyan, Liu, Wenjing, Zhu, Xianjun. 2022. Deletion of Asrgl1 Leads to Photoreceptor Degeneration in Mice. In Frontiers in cell and developmental biology, 9, 783547. doi:10.3389/fcell.2021.783547. https://pubmed.ncbi.nlm.nih.gov/35118070/

4. Xue, Cailin, Gao, Peng, Cui, Xiaohan, Zhu, Chunfu, Qin, Xihu. 2021. ASRGL1 Correlates With Immune Cell Infiltration in Hepatocellular Carcinoma and Can Serve as a Prognostic Biomarker. In Frontiers in oncology, 11, 680070. doi:10.3389/fonc.2021.680070. https://pubmed.ncbi.nlm.nih.gov/34249720/

5. Biswas, Pooja, Berry, Anne Marie, Zawaydeh, Qais, Riazuddin, S Amer, Ayyagari, Radha. 2022. A Mouse Model with Ablated Asparaginase and Isoaspartyl Peptidase 1 (Asrgl1) Develops Early Onset Retinal Degeneration (RD) Recapitulating the Human Phenotype. In Genes, 13, . doi:10.3390/genes13081461. https://pubmed.ncbi.nlm.nih.gov/36011372/

6. Biswas, Pooja, Chavali, Venkata Ramana Murthy, Agnello, Giulia, Riazuddin, S Amer, Ayyagari, Radha. 2016. A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. In Human molecular genetics, 25, 2483-2497. doi:. https://pubmed.ncbi.nlm.nih.gov/27106100/