ITRAQ-based proteomic profiling reveals protein alterations after traumatic brain injury and supports thyroxine as a potential treatment

Zhongxiang Zhang,Rong Zeng,Haoli Ma,Ruining Liu,Pengcheng Wang,Yan Zhao,Lian Lin,Jiangtao Yu

doi:10.1186/s13041-021-00739-0

Zhongxiang Zhang, Rong Zeng + Show 6 more

Open Access

https://doi.org/10.1186/s13041-021-00739-0

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Abstract

Traumatic brain injury (TBI) is a primary cause of disability and death across the world. Previously, RNA analysis was widely used to study the pathophysiological mechanisms underlying TBI; however, the relatively low correlation between the transcriptome and proteome revealed that RNA transcription abundance does not reliably predict protein abundance, which led to the emergence of proteomic research. In this study, an iTRAQ proteomics approach was applied to detect protein alterations after TBI on a large scale. A total of 3937 proteins were identified, and 146 proteins were significantly changed after TBI. Moreover, 23 upregulated proteins were verified by parallel reaction monitoring (PRM), and fold changes in 16 proteins were consistent with iTRAQ outcomes. Transthyretin (Ttr) upregulation has been demonstrated at the transcriptional level, and this study further confirmed this at the protein level. After treatment with thyroxine (T4), which is transported by Ttr, the effects of T4 on neuronal histopathology and behavioral performance were determined in vivo (TBI + T4 group). Brain edema was alleviated, and the integrity of the blood brain barrier (BBB) improved. Escape latency in the Morris water maze (MWM) declined significantly compared with the group without T4 treatment. Modified neurological severity scores (mNSS) of the TBI + T4 group decreased from day 1 to day 7 post-TBI compared with the TBI + saline group. These results indicate that T4 treatment has potential to alleviate pathologic and behavioral abnormalities post-TBI. Protein alterations after T4 treatment were also detected by iTRAQ proteomics. Upregulation of proteins like Lgals3, Gfap and Apoe after TBI were reversed by T4 treatment. GO enrichment showed T4 mainly affected intermediate filament organization, cholesterol transportation and axonal regeneration. In summary, iTRAQ proteomics provides information about the impact of TBI on protein alterations and yields insight into underlying mechanisms and pathways involved in TBI and T4 treatment. Finally, Ttr and other proteins identified by iTRAQ may become potential novel treatment targets post-TBI.

Highlights

Traumatic brain injury (TBI) is caused by an external force damaging the brain and is a major cause of disability and death in the United States [1]
The top five proteins based on the fold change included Hspa4, Alb, Hemoglobin subunit alpha-1/2 (Hba1), Hemoglobin subunit beta-1 (Hbb), and Krt42
The top five proteins based on the p-value included Krt10, S100a8, Mug1, Hpx, and Group specific component (Gc) (Fig. 2c)

Summary

Introduction

Traumatic brain injury (TBI) is caused by an external force damaging the brain and is a major cause of disability and death in the United States [1]. Zhang et al Mol Brain (2021) 14:25 from TBI at a higher prevalence [3, 4]. The pathophysiology of TBI-related injury is divided into primary and secondary brain injury. Secondary brain injury is characterized by a series of pathophysiological processes including electrolyte imbalance [5], mitochondrial dysfunction [6], neuroinflammation [7], brain edema [8], and cerebral vascular injury [9]. Current treatment of TBI is still primarily based on symptomatic treatment, focusing on acute management instead of specific medicinal therapy targeting the pathways involved in post-TBI pathophysiology [10]. Further research is required to elucidate the mechanisms underlying TBI and identify suitable therapeutic targets in order to determine more precise and potent clinical treatment methods

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