Arpp21, or cAMP Regulated Phosphoprotein 21, is an RNA-binding protein. It plays crucial roles in multiple biological processes. In thymocytes, it is involved in the regulation of T-cell receptor (TCR) repertoire diversity. It also has implications in neurological function repair and is associated with neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) [1,2,3]. Genetic models such as knockout (KO) mouse models are valuable for studying its functions.

In thymocyte-specific Arpp21-deficient mice, reduced Rag1 expression, delayed TCR rearrangement, and a less diverse TCR repertoire were observed. This indicates that Arpp21 promotes Rag1 expression by binding to the 3'-UTR of Rag1 mRNA to enable TCR repertoire diversity until TCR signals terminate its activity [1]. In ALS-related studies, a missense mutation (c.1586C>T; p.Pro529Leu) in Arpp21 was identified in Spanish patients with ALS, and a novel ARPP21 c.1231G>A (p.Glu411Lys) variant was found in a Chinese ALS-frontotemporal dementia (FTD) patient, suggesting its potential role in ALS pathogenesis [4,5].

In summary, Arpp21 is essential for TCR repertoire diversity in thymocytes. Its study through KO/CKO mouse models has provided insights into its role in thymocyte development. In the context of ALS, genetic analysis in different patient cohorts has revealed potential disease-associated mutations, highlighting its significance in understanding the genetic mechanisms of this neurodegenerative disease.

References:

1. Xu, Meng, Ito-Kureha, Taku, Kang, Hyun-Seo, Łyszkiewicz, Marcin, Heissmeyer, Vigo. 2024. The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression. In Nature communications, 15, 2194. doi:10.1038/s41467-024-46371-z. https://pubmed.ncbi.nlm.nih.gov/38467629/

2. Chai, Zhaohui, Zheng, Peidong, Zheng, Jiesheng. 2021. Mechanism of ARPP21 antagonistic intron miR-128 on neurological function repair after stroke. In Annals of clinical and translational neurology, 8, 1408-1421. doi:10.1002/acn3.51379. https://pubmed.ncbi.nlm.nih.gov/34047500/

3. Wang, Hui, Guan, LiPing, Deng, Min. 2023. Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy. In Frontiers in neuroscience, 17, 1170996. doi:10.3389/fnins.2023.1170996. https://pubmed.ncbi.nlm.nih.gov/37250416/

4. Dols-Icardo, Oriol, Carbayo, Álvaro, Jericó, Ivonne, Gelpi, Ellen, Rojas-García, Ricard. 2025. Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis. In Journal of neurology, neurosurgery, and psychiatry, 96, 132-139. doi:10.1136/jnnp-2024-333834. https://pubmed.ncbi.nlm.nih.gov/38960585/

5. Wang, Yiying, Ju, Runqing, Jiang, Jingsi, Li, Xiaogang, Deng, Min. 2024. Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients. In Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 46, 195-205. doi:10.1007/s10072-024-07759-3. https://pubmed.ncbi.nlm.nih.gov/39271636/