Quantitative Proteomic Study Reveals Up-Regulation of cAMP Signaling Pathway-Related Proteins in Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI), as a neurological injury, becomes a leading cause of disability and mortality due to lacking effective therapy. About 75% of TBI is mild traumatic brain injury (mTBI). However, the complex molecular mechanisms underlying mTBI pathophysiology remains to be elucidated. In this study, iTRAQ-based quantitative proteomic approach was employed to measure temporal-global proteome changes of rat brain tissues from different time points (1 day, 7 day and 6 months) post single mTBI (smTBI) and repetitive mTBI (rmTBI). A total of 5169 proteins were identified, of which, 237 proteins were significantly changed between control rats and mTBI model rats. Fuzzy c-means (FCM) clustering analysis classified these 237 proteins into six clusters according to their temporal pattern of protein abundance. Functional bioinformatics analysis and protein-protein interaction (PPI) network mapping of these FCM clusters showed that phosphodiesterase 10A (Pde10a) and guanine nucleotide-binding protein G (olf) subunit alpha (Gnal) were the node proteins in the cAMP signaling pathway. Other biological processes, such as cell adhesion, autophagy, myelination, microtubule depolymerization and brain development, were also over-represented in FCM clusters. Further Western Blot experiments confirmed that Pde10a and Gnal were acutely up-regulated in severity-dependent manner by mTBI, but these two proteins could not be down-regulated to basal level at the time point of 6 months post repetitive mTBI. Our study demonstrated that different severity of mTBI cause significant temporal profiling change at the proteomic level and pointed out the cAMP signaling pathway-related proteins, Pde10a and Gnal, may play important roles in the pathogenesis and recovery of mTBI.

Continuous High Frequency Deep Brain Stimulation of the Rat Anterior Insula Attenuates the Relapse Post Withdrawal and Strengthens the Extinction of Morphine Seeking

“…Gα olf is a subunit of trimeric GTP-binding protein (G-protein) stimulating adenylyl cyclase enzymes, which regulate the cAMP signaling pathway and further modulate brain functions such as synaptic plasticity drug dependence ( 59 , 61 ). In the rat brain, Gα olf is mainly expressed in olfactory neurons and striatum ( 62 ), but it is also present in other sub-regions including the pre-frontal cortex ( 63 ). In agreement with our results, a previous study has shown that chronic morphine treatment decreases the expression of Gα olf in the striatal presynaptic fractions of rats ( 57 ).…”

Proteomic changes in traumatic brain injury: experimental approaches

“…To examine the global proteome effects of repetitive TBI, Song et al [ 3 ▪▪ ] used a unique rat model of repetitive mild brain injury. The repetitive groups were impacted once per day for 3 consecutive days.…”

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau

“…Proteomic research [21, 22] using brain tissues or biofluids from either patients or animal models have made it feasible to identify a large number of proteins associated with mTBI [23,24]. MS-based proteomics possess the advantage of having no requirement of prior knowledge of the proteins being identified, allowing for unbiased, hypothesis-free biomarker discovery in complex biological samples such as plasma and brain tissue extracts.…”