Jewett Michael, Dickson Elna, Brolin Kajsa, Negrini Matilde, Jimenez-Ferrer Itzia, Swanberg Maria
Translational Neurogenetics Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Front Neurol. 2018 Apr 6;9:222. doi: 10.3389/fneur.2018.00222. eCollection 2018.
Parkinson's disease (PD) is a common, progressive neurodegenerative disease, which typically presents itself with a range of motor symptoms, like resting tremor, bradykinesia, and rigidity, but also non-motor symptoms such as fatigue, constipation, and sleep disturbance. Neuropathologically, PD is characterized by loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and Lewy bodies, neuronal inclusions containing α-synuclein (α-syn). Mutations and copy number variations of , the gene encoding α-syn, are linked to familial PD and common gene variants are associated to idiopathic PD. Large-scale genome-wide association studies have identified risk variants across another 40 loci associated to idiopathic PD. These risk variants do not, however, explain all the genetic contribution to idiopathic PD. The rat locus has been linked to neuroprotection after nerve- and brain injury in rats. includes the glutathione -transferase alpha 4 () gene, which encodes a protein involved in clearing lipid peroxidation by-products. The DA.VRA1 congenic rat strain, carrying PVG alleles in on a DA strain background, was recently reported to express higher levels of transcripts and to display partial neuroprotection of SNpc dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) induced model for PD. Since α-syn expression increases the risk for PD in a dose-dependent manner, we assessed the neuroprotective effects of in an α-syn-induced PD model. Human wild-type α-syn was overexpressed by unilateral injections of the rAAV6-α-syn vector in the SNpc of DA and DA.VRA1 congenic rats. gene expression levels were significantly higher in the striatum and midbrain of DA.VRA1 compared to DA rats at 3 weeks post surgery, in both the ipsilateral and contralateral sides. At 8 weeks post surgery, DA.VRA1 rats suffered significantly lower fiber loss in the striatum and lower loss of dopaminergic neurons in the SNpc compared to DA. Immunofluorescent stainings showed co-expression of Gsta4 with Gfap at 8 weeks suggesting that astrocytic expression of Gsta4 underlies -mediated neuroprotection to α-syn induced pathology. This is the second PD model in which is linked to protection of the nigrostriatal pathway, solidifying Gsta4 as a potential therapeutic target in PD.
帕金森病（PD）是一种常见的进行性神经退行性疾病，通常表现出一系列运动症状，如静止性震颤、运动迟缓及僵硬，还伴有非运动症状，如疲劳、便秘和睡眠障碍。在神经病理学上，PD的特征是黑质致密部（SNpc）多巴胺能细胞的丧失以及路易小体，即含有α-突触核蛋白（α-syn）的神经元内含物。编码α-syn的基因的突变和拷贝数变异与家族性PD相关，常见的基因变异与特发性PD相关。大规模全基因组关联研究已经在另外40个与特发性PD相关的基因座中鉴定出风险变异。然而，这些风险变异并不能解释特发性PD的所有遗传因素。大鼠的基因座与大鼠神经和脑损伤后的神经保护有关。该基因座包括谷胱甘肽-S-转移酶α4（Gsta4）基因，其编码一种参与清除脂质过氧化副产物的蛋白质。最近报道，携带PVG等位基因的DA.VRA1同源大鼠品系在DA品系背景下，在6-羟基多巴胺（6-OHDA）诱导的PD模型中，表达更高水平的Gsta4转录本，并对SNpc多巴胺能神经元表现出部分神经保护作用。由于α-syn的表达以剂量依赖的方式增加PD的风险，我们在α-syn诱导的PD模型中评估了Gsta4的神经保护作用。通过向DA和DA.VRA1同源大鼠的SNpc单侧注射rAAV6-α-syn载体来过表达人野生型α-syn。术后3周，DA.VRA1大鼠纹状体和中脑的Gsta4基因表达水平在同侧和对侧均显著高于DA大鼠。术后8周，与DA大鼠相比，DA.VRA1大鼠纹状体中的纤维损失显著更低，SNpc中的多巴胺能神经元损失也更低。免疫荧光染色显示，术后8周Gsta4与胶质纤维酸性蛋白（Gfap）共表达，这表明Gsta4的星形细胞表达是Gsta4介导的针对α-syn诱导病理的神经保护作用的基础。这是第二个将Gsta4与黑质纹状体通路保护联系起来的PD模型，巩固了Gsta4作为PD潜在治疗靶点的地位。
