Tpp2, or tripeptidyl peptidase II, is a serine peptidase ubiquitously expressed. It is a cytosolic protein that forms a large protease complex in eukaryotic cells, mainly acting downstream of proteasomes to remove tripeptides from the N-terminal end of longer peptides. It is involved in various biological processes such as major histocompatibility complex Class I epitope destruction, amino acid homeostasis, and is associated with pathways related to immune and neurological functions [2,3,4].

In TPP2 knockout mouse models, TPP2 was found to be crucial for maintaining the homeostasis of intracellular Ca2+ and phosphatidylcholine (PC) in the central nervous system (CNS). Its depletion led to presenile dementia in female mice, associated with Ca2+/PC dysregulation-induced endoplasmic reticulum (ER) stress, abnormal autophagic degradation of CYP19A1, and estrogen depletion [1]. Also, homozygous missense mutations in TPP2 in humans were related to sterile brain inflammation mimicking MS, and biallelic variants were associated with immune deficiency, autoimmune cytopenias, and intellectual disability [2,3].

In conclusion, Tpp2 plays essential roles in maintaining calcium and lipid homeostasis in the CNS, and in immune-related functions. Studies using gene knockout models have revealed its significance in conditions like presenile dementia, sterile brain inflammation, immune deficiency, and autoimmune diseases, providing valuable insights into the pathogenesis of these disorders [1,2,3].