Abstract
Idiopathic Parkinson’s disease (PD) is a complex disease caused by multiple, mainly unknown, genetic and environmental factors. The Ventral root avulsion 1 (Vra1) locus on rat chromosome 8 includes the Glutathione S-transferase alpha 4 (Gsta4) gene and has been identified in crosses between Dark Agouti (DA) and Piebald Virol Glaxo (PVG) rat strains as being associated to neurodegeneration after nerve and brain injury. The Gsta4 protein clears lipid peroxidation by-products, a process suggested to being implicated in PD. We therefore investigated whether PVG alleles in Vra1 are neuroprotective in a toxin-induced model of PD and if this effect is coupled to Gsta4. We performed unilateral 6-hydroxydopamine (6-OHDA) partial lesions in the striatum and compared the extent of neurodegeration in parental (DA) and congenic (DA.VRA1) rats. At 8 weeks after 6-OHDA lesion, DA.VRA1 rats displayed a higher density of remaining dopaminergic fibers in the dorsolateral striatum compared to DA rats (44% vs. 23%, p < 0.01), indicating that Vra1 alleles derived from the PVG strain protect dopaminergic neurons from 6-OHDA toxicity. Gsta4 gene expression levels in the striatum and midbrain were higher in DA.VRA1 congenic rats compared to DA at 2 days post-lesion (p < 0.05). The GSTA4 protein co-localized with astrocytic marker GFAP, but not with neuronal marker NeuN or microglial marker IBA1, suggesting astrocyte-specific expression. This is the first report on Vra1 protective effects on dopaminergic neurodegeneration and encourages further studies on Gsta4 in relation to PD susceptibility.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a range of motor and non-motor symptoms
6-OHDA lesion, Dark Agouti (DA).VRA1 rats displayed a higher density of remaining dopaminergic fibers in the dorsolateral striatum compared to DA rats (44% vs. 23%, p < 0.01), indicating that Ventral root avulsion 1 (Vra1) alleles derived from the Piebald Virol Glaxo (PVG) strain protect dopaminergic neurons from 6-OHDA toxicity
Our results show that PVG.1AV1 alleles in Vra1 are neuroprotective in the 6-OHDA PD model, and suggest that this effect is mediated by increased GSTA4 expression in astrocytes
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a range of motor and non-motor symptoms. Brain Sci. 2017, 7, 73 rodent strains [7] Once these genetic regions are identified, functional experimental analyses can be used to examine the impact of these regions on disease processes. 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]. Intraparenchymal injections of 6-OHDA to the brain target the nigrostriatal pathway, making 6-OHDA a viable tool for studying neurodegenerative processes, especially those related to PD and oxidative stress. We hypothesized that the Vra locus encoding Gsta in the DA.VRA1 strain protects the nigrostriatal pathway after unilateral striatal 6-OHDA injections To test this hypothesis, we compared the extent of dopaminergic neurodegeneration in the striatum and SNpc in DA and DA.VRA1 rats. Our results show that PVG.1AV1 alleles in Vra are neuroprotective in the 6-OHDA PD model, and suggest that this effect is mediated by increased GSTA4 expression in astrocytes
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