Activity-Based Proteome Profiling of Serum Serine Hydrolases: Application in Pediatric Abusive Head Trauma
Estelle Maret1,2, Kim Wiskott3, Tobias Shipley1
1Faculty Unit of Toxicology, University Center of Legal Medicine, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Insights
This study found reduced activity of serine hydrolases in the blood serum of infants with abusive head trauma (AHT). This discovery could aid in diagnosing AHT, especially milder cases, improving outcomes for pediatric traumatic brain injury (TBI).
Area of Science:
- Biochemistry
- Neuroscience
- Pediatric Medicine
Background:
- Traumatic brain injury (TBI), including pediatric abusive head trauma (AHT), is a major cause of child mortality and disability.
- Understanding molecular changes in the brain after intracranial hemorrhage (ICH) is crucial for improving TBI management.
- Calcium-mediated damage in brain injuries activates various enzymes, including serine hydrolases (SHs).
Purpose of the Study:
- To investigate the activity status of serine hydrolases (SHs) in the serum of infants with severe intracranial hemorrhage (ICH) due to abusive head trauma (AHT).
- To compare SH enzyme activity in infants with AHT-related ICH to that of infants who died from sudden infant death syndrome (SIDS).
- To explore the potential of activity-based protein profiling (ABPP) for detecting molecular changes in pediatric TBI.
Main Methods:
- Activity-based protein profiling (ABPP) was employed to measure the activity of SH enzymes.
- Liquid chromatography-mass spectrometry (LC-MS) was used in conjunction with ABPP.
- Serum samples from infants under 2 years old were analyzed: those with severe AHT-induced ICH and a control group of SIDS infants.
Main Results:
- Dozens of metabolic SHs showed significantly reduced physiological activity in the serum of infants with severe AHT compared to the SIDS group.
- Several identified SHs are involved in neurodevelopment and basic brain metabolism.
- This proof-of-principle study identified a distinct biochemical signature in AHT-affected infants.
Conclusions:
- This is the first study to use ABPP to assess SH enzyme activity in serum from infants with severe TBI.
- Reduced serum serine lipase activities were observed in AHT cases.
- The ABPP approach shows promise for further investigation in milder forms of AHT, potentially improving the diagnosis of currently misdiagnosed cases.
Purpose:
Traumatic brain injury (TBI), including pediatric abusive head trauma (AHT), is the leading cause of death and disability in children and young adults worldwide. The current understanding of trauma-induced molecular changes in the brain of human subjects with intracranial hemorrhage (ICH) remains inadequate and requires further investigation to improve the outcome and management of TBI in the clinic. Calcium-mediated damage at the site of brain injury has been shown to activate several catalytic enzymes.
Experimental Design:
Serine hydrolases (SHs) are major catalytic enzymes involved in the biochemical pathways of blood coagulation, systemic inflammation, and neuronal signaling. Here, we investigated activity-based protein profiling (ABPP) coupled to liquid chromatography-mass spectrometry (LC-MS) by measuring the activity status of SH enzymes in the serum of infants with severe ICH as a consequence of AHT or atraumatic infants who died of sudden infant death syndrome (SIDS).
Results:
Our proof-of-principle study revealed significantly reduced physiological activity of dozens of metabolic SHs in the serum of infants with severe AHT compared to the SIDS group, with some of the enzymes being related to neurodevelopment and basic brain metabolism.
Conclusions And Clinical Relevance:
To our knowledge, this is the first study to investigate the ABPP of the SHs enzyme family to detect changes in their physiological activity in blood serum in severe TBI. We used antemortem (AM) serum from infants under the age of 2 years who were victims of AHT with a severe form of ICH. The analytical approach used in the proof-of-principle study shows reduced activities of serum serine lipases in AHT cases and could be further investigated in mild forms of AHT, which currently show 30% of misdiagnosed cases in clinics.
