Arpp21, also known as 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 through promoting Rag1 mRNA expression. It also has potential functions in neurological function repair, and has been associated with neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) [1,2,3].

In thymocyte-specific studies, Arpp21-deficient thymocytes showed reduced Rag1 expression, delayed TCR rearrangement, and a less diverse TCR repertoire, indicating its importance in TCR repertoire diversity [1]. Regarding ALS, while some studies did not find significant associations between ARPP21 mutations and ALS in Australian and Chinese cohorts, a recent study identified a pathogenic mutation (c.1586C>T; p.Pro529Leu) in ARPP21 in Spanish ALS patients, strongly supporting it as a novel ALS-causing gene. Also, a novel ARPP21 c.1231G > A (p.Glu411Lys) variant was found in a Chinese ALS-frontotemporal dementia (FTD) patient, providing fresh evidence for the association between ARPP21 and ALS [4,5,6,7].

In conclusion, Arpp21 is essential for TCR repertoire diversity in thymocytes. Its role in neurodegenerative diseases, especially ALS, is emerging. The use of gene-knockout or conditional-knockout mouse models in thymocyte studies has clearly demonstrated its function in TCR-related processes. In the context of ALS, the identification of mutations in ARPP21 through genetic analysis in different patient cohorts contributes to understanding the genetic mechanisms underlying the disease.