Tpp2, also known as tripeptidyl peptidase II, is a serine peptidase. It is generally considered a cytosolic protein that forms the largest known protease complex in eukaryotic cells, mainly operating downstream of proteasomes to degrade longer peptides. Tpp2 is involved in various biological processes such as DNA repair, cellular division, apoptosis, and the destruction of major histocompatibility complex Class I epitopes. It also plays a role in amino acid homeostasis and is associated with pathways related to immune response and neural function [2,3,4]. Genetic models, like knockout (KO) and conditional knockout (CKO) mouse lines, have been crucial in studying its functions.

In a TPP2 knockout mouse model, TPP2 was found to play a crucial role in maintaining the homeostasis of intracellular Ca2+ and phosphatidylcholine (PC) in the central nervous system (CNS) independent of its enzymatic activity. Its gene ablation caused presenile dementia in female mice, linked to Ca2+/PC dysregulation-induced endoplasmic reticulum stress, abnormal autophagic degradation of CYP19A1, and estrogen depletion [1]. In addition, homozygous missense mutations in TPP2 in humans were associated with sterile brain inflammation mimicking MS, and a 4.4 Kb deletion removing exons 20-23 of the TPP2 gene led to a multisystemic condition with immune system dysregulation and intellectual disability [2,3].

In conclusion, Tpp2 is essential for maintaining calcium and lipid homeostasis in the CNS, and its deficiency can lead to sexual dimorphism in dementia. The study of Tpp2 KO/CKO mouse models has significantly contributed to understanding the pathogenesis of dementia and related disorders, as well as the role of Tpp2 in immune-related diseases and intellectual disability [1,2,3].

References:

1. Zhao, Jin, He, Chengtong, Fan, Xueyu, Tong, Jia, Huai, Jisen. 2024. Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1. In Theranostics, 14, 1390-1429. doi:10.7150/thno.92571. https://pubmed.ncbi.nlm.nih.gov/38389851/

2. Reinthaler, Eva M, Graf, Elisabeth, Zrzavy, Tobias, Lassmann, Hans, Zimprich, Alexander. 2018. TPP2 mutation associated with sterile brain inflammation mimicking MS. In Neurology. Genetics, 4, e285. doi:10.1212/NXG.0000000000000285. https://pubmed.ncbi.nlm.nih.gov/30533531/

3. Atallah, Isis, Quinodoz, Mathieu, Campos-Xavier, Belinda, Unger, Sheila, Superti-Furga, Andrea. 2021. Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene. In Clinical genetics, 99, 780-788. doi:10.1111/cge.13942. https://pubmed.ncbi.nlm.nih.gov/33586135/

4. Usukura, Katsuya, Kasamatsu, Atsushi, Okamoto, Atsushi, Tanzawa, Hideki, Uzawa, Katsuhiro. 2012. Tripeptidyl peptidase II in human oral squamous cell carcinoma. In Journal of cancer research and clinical oncology, 139, 123-30. doi:10.1007/s00432-012-1307-y. https://pubmed.ncbi.nlm.nih.gov/22986808/