Arpp21, or cAMP Regulated Phosphoprotein 21, is an RNA-binding protein with diverse functions. It has been associated with regulating thymocyte development and neurological functions. In thymocytes, it is involved in the T-cell receptor (TCR) repertoire diversity pathway, and in neurons, it may play a role in stroke-related neurological function repair [1,2]. Genetic models can be valuable in further exploring its functions.

In thymocyte-specific studies, Arpp21-deficient thymocytes showed reduced Rag1 expression, delayed TCR rearrangement, and a less diverse TCR repertoire. This phenotype was also seen in Rag1 3'-UTR mutant mice with a deletion of the Arpp21 response region, indicating Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until TCR signals terminate its activity [1]. Regarding neurological function, while a study on the role of Arpp21 in stroke-related neurological function repair was retracted due to image issues, it initially proposed that Arpp21 upregulated CREB1 and BDNF expressions by antagonizing miR-128, thus inhibiting neuronal apoptosis and promoting repair [2,6]. In ALS research, different studies had varying results. Some found no significant association between ALS and ARPP21 in Australian and Chinese cohorts [3,4], while others identified a pathogenic mutation in ARPP21 in Spanish ALS patients and a novel variant in Chinese ALS-FTD patients, suggesting its potential role in ALS [5,7].

In conclusion, Arpp21 plays essential roles in thymocyte development by contributing to TCR repertoire diversity. Its role in neurological function, especially related to stroke and neurodegenerative diseases like ALS, is still being explored. Gene-knockout or conditional-knockout mouse models, such as those used in thymocyte studies, have been crucial in revealing its functions in specific biological processes and may further contribute to understanding its role in disease conditions.

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. Chan Moi Fat, Sandrine, McCann, Emily P, Williams, Kelly L, Fifita, Jennifer A, Blair, Ian P. 2021. Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis. In Neurobiology of aging, 101, 297.e9-297.e11. doi:10.1016/j.neurobiolaging.2021.01.005. https://pubmed.ncbi.nlm.nih.gov/33581934/

4. Li, Wanzhen, Liu, Zhen, Sun, Weining, Tang, Beisha, Wang, Junling. 2019. Mutation analysis of GLT8D1 and ARPP21 genes in amyotrophic lateral sclerosis patients from mainland China. In Neurobiology of aging, 85, 156.e1-156.e4. doi:10.1016/j.neurobiolaging.2019.09.013. https://pubmed.ncbi.nlm.nih.gov/31653410/

5. 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/

6. . 2024. RETRACTION: Mechanism of ARPP21 antagonistic intron miR-128 on neurological function repair after stroke. In Annals of clinical and translational neurology, 11, 1948. doi:10.1002/acn3.52086. https://pubmed.ncbi.nlm.nih.gov/38767306/

7. 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/