Chemical Proteomic Analysis of Serine Hydrolase Activity in Niemann-Pick Type C Mouse Brain

Frontiers in Neuroscience

Bogdan I. Florea¹  Herman S. Overkleeft¹  Roelof Ottenhoff²  André R. A. Marques³  Rolf G. Boot⁴  Johannes M. F. G. Aerts⁴  Hui Deng⁵  Eva J. van Rooden⁵  Annelot C. M. van Esbroeck⁵  Marc P. Baggelaar⁵  Mario van der Stelt⁵ 

[1] Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands;Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands;Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany;Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands;Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands;

关键词: chemical proteomics;    activity-based protein profiling;    endocannabinoid system;    hydrolases;    Niemann-Pick type C;   

DOI  :  10.3389/fnins.2018.00440

来源: DOAJ

【 摘 要 】

The endocannabinoid system (ECS) is considered to be an endogenous protective system in various neurodegenerative diseases. Niemann-Pick type C (NPC) is a neurodegenerative disease in which the role of the ECS has not been studied yet. Most of the endocannabinoid enzymes are serine hydrolases, which can be studied using activity-based protein profiling (ABPP). Here, we report the serine hydrolase activity in brain proteomes of a NPC mouse model as measured by ABPP. Two ABPP methods are used: a gel-based method and a chemical proteomics method. The activities of the following endocannabinoid enzymes were quantified: diacylglycerol lipase (DAGL) α, α/β-hydrolase domain-containing protein 4, α/β-hydrolase domain-containing protein 6, α/β-hydrolase domain-containing protein 12, fatty acid amide hydrolase, and monoacylglycerol lipase. Using the gel-based method, two bands were observed for DAGL α. Only the upper band corresponding to this enzyme was significantly decreased in the NPC mouse model. Chemical proteomics showed that three lysosomal serine hydrolase activities (retinoid-inducible serine carboxypeptidase, cathepsin A, and palmitoyl-protein thioesterase 1) were increased in Niemann-Pick C1 protein knockout mouse brain compared to wild-type brain, whereas no difference in endocannabinoid hydrolase activity was observed. We conclude that these targets might be interesting therapeutic targets for future validation studies.

【 授权许可】

Unknown