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

作者：Jin Zhao, Chengtong He, Xueyu Fan, Lin Wang, Liao Zhao, Hui Liu, Wujun Shen, Sanwei Jiang, Kaixuan Pei, Jingjing Gao, Yawei Qi, Yang Liu, Junqiang Zhao, Ruiling Zhang, Chengbiao Lu, Jia Tong, Jisen Huai · 发表于：Theranostics · 年份：2024 · DOI：10.7150/thno.92571 · 被引用次数：8 · 研究领域：Macrophage Migration Inhibitory Factor、Nuclear Receptors and Signaling、Adenosine and Purinergic Signaling

Rationale: Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms the largest known protease complex in eukaryotic cells to operate mostly downstream of proteasomes for degradation of longer peptides. However, this canonical function of TPP2 cannot explain its role in a wide variety of biological and pathogenic processes. The mechanistic interrelationships and hierarchical order of these processes have yet to be clarified. Methods: Animals, cells, plasmids, and viruses established and/or used in this study include: TPP2 knockout mouse line, TPP2 conditional knockout mouse lines (different neural cell type oriented), TRE-TPP2 knockin mouse line on the C57BL/6 background; 293T cells with depletion of TPP2, ATF6, IRE1, PERK, SYVN1, UCHL1, ATG5, CEPT1, or CCT, respectively; 293T cells stably expressing TPP2, TPP2 S449A, TPP2 S449T, or CCT-KDEL proteins on the TPP2-depleted background; Plasmids for eukaryotic transient expression of rat CYP19A1-Flag, CYP19A1 S118A-Flag, CYP19A1 S118D-Flag, Sac I ML GFP Strand 11 Long, OMMGFP 1-10, G-CEPIA1er, GCAMP2, CEPIA3mt, ACC-GFP, or SERCA1-GFP; AAV2 carrying the expression cassette of mouse CYP19A1-3 X Flag-T2A-ZsGreen. Techniques used in this study include: Flow cytometry, Immunofluorescence (IF) staining, Immunohistochemical (IHC) staining, Luxol fast blue (LFB) staining, -galactosidase staining, Lipid droplet (LD) staining, Calc...