Naturally Occurring Variation in the Glutathione-S-Transferase 4 Gene Determines Neurodegeneration After Traumatic Brain Injury

Abstract

Aim: Genetic factors are important for outcome after traumatic brain injury (TBI), although exact knowledge of relevant genes/pathways is still lacking. We here used an unbiased approach to define differentially activated pathways between the inbred DA and PVG rat strains. The results prompted us to study further if a naturally occurring genetic variation in glutathione-S-transferase alpha 4 (Gsta4) affects the outcome after TBI. Results: Survival of neurons after experimental TBI is increased in PVG compared to the DA strain. Global expression profiling analysis shows the glutathione metabolism pathway to be the most regulated between the strains, with increased Gsta4 in PVG among top regulated transcripts. A congenic strain (R5) with a PVG genomic insert containing the Gsta4 gene on DA background displays a reversal of the strain pattern for Gsta4 expression and increased survival of neurons compared to DA. Gsta4 is known to effectively reduce 4-hydroxynonenal (4-HNE), a noxious by-product of lipid peroxidation. Immunostaining of 4-HNE was evident in both rat and human TBI. Intracerebral injection of 4-HNE resulted in neurodegeneration with increased levels of a marker for nerve injury in cerebrospinal fluid of DA compared to R5. Innovation: These findings provide strong support for the notion that the inherent capability of coping with increased 4-HNE after TBI affects outcome in terms of nerve cell loss. Conclusion: A naturally occurring variation in Gsta4 expression in rats affects neurodegeneration after TBI. Further studies are needed to explore if genetic variability in Gsta4 can be associated to outcome also in human TBI. Antioxid. Redox Signal. 18, 784-794.

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…Lastly, a recent study clearly demonstrates that intracerebral injection of HNE results in neurodegeneration. 35 Therefore, HNE can impair key areas in the brain, leading to neuronal cell death. Carnosine, as a carbonyl scavenger and antioxidant, can provide protection against HNE and decrease neurodegenerative disorders, 36 but its action is not limited to HNE-dependent damage.…”

Therapies targeting lipid peroxidation in traumatic brain injury

“…In this section we will briefly review detection of lipid peroxidation in clinical TBI. Lipid peroxidation end products such as malondialdehyde, 4-HNE and isoprostanes have been shown to increase in bio-fluids and brain tissue samples from TBI patients (Al Nimer et al, 2013; Cristofori et al, 2001; Cristofori et al, 2005; Kasprzak et al, 2001; Lin et al, 2014b; Lorente et al, 2015; Niki, 2014). Despite criticism for lack of specificity and artefactual production during analytical processing, malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS) remain the most commonly used markers of lipid peroxidation in clinical TBI, and their increase in cerebrospinal fluid (CSF) and serum have been associated with severity of injury and mortality (Cristofori et al, 2001; Cristofori et al, 2005; Kasprzak et al, 2001; Lin et al, 2014b; Lorente et al, 2015).…”

“…It forms covalent adducts with proteins and can be detected by immunohistochemistry (Niki, 2014). A recent study reported that 4-HNE-conjugates are present in neurons in human TBI but were not detected in CSF (Al Nimer et al, 2013). …”

Astrocytic Expression of GSTA4 Is Associated to Dopaminergic Neuroprotection in a Rat 6-OHDA Model of Parkinson’s Disease

“…This strain was used to finely map Vra1 , and several candidate genes were discovered [ 9 ]. A later study determined Glutathione S -transferase alpha 4 ( Gsta4 ) as the strongest candidate gene regulating neurodegeneration in response to VRA [ 10 ] and traumatic brain injury (TBI) in DA.VRA1 congenic rats [ 11 ].…”