Massive solubility changes of neuronal proteins upon simulated traumatic brain injury reveal the role of shockwave in irreversible damage

Abstract

The immediate molecular consequences of traumatic brain injuries or TBI are poorly understood. Here, we simulated TBI using an innovative laboratory apparatus that employs a 5.1 kg dummy head holding neuronal cells and generating a less than or equal to 4,000 g-force acceleration upon impact. Dynamic impact led to both reduction in neuron viability and massive solubility changes in the proteome profiled using Proteome Integral Solubility Alteration (PISA) assay. The affected proteins mapped not only to the expected pathways like cell adhesion, collagen and laminin structures, as well as response to stress, but also to other dense protein networks, such as immune response, complement and coagulation cascades. The cellular effects are found to be mainly due to the shockwave rather than the g-force acceleration. Soft materials could reduce the impact severity only until being fully compressed. This study shows way to develop a proteome-based meter for measuring irreversible shockwave-induced cell damage and provides a resource for identifying TBI protein biomarkers and potential drug targets for developing products aiming at primary prevention and intervention.

ThermoTargetMiner as a proteome integral solubility alteration target database for prospective drugs against lung cancer

“…We have previously applied PISA for protein target identification and exploring mechanisms of small-molecule drugs 6,12 , biomarker discovery 16 , as well as for identification and prioritization of enzyme substrates 15,17 . In the current study, we tested the PISA performance as a higher-throughput technique for reliable drug target deconvolution on a larger set of drugs, choosing lung cancer as the application field (Figure 1).…”