THERAPEUTIC APPROACHES FOR NEURODEGENERATION CAUSED BY PLA2G6 MUTATIONS

描述(申请人提供)：PLA2G6基因突变会导致幼年型神经退行性疾病，被归类为婴儿神经轴索营养不良(INAD)或伴有脑铁积聚的神经退行性变(NBIA)。这两种疾病具有重叠的特征，涉及运动、言语和认知的进行性损害。PLA2G6基因通过钙非依赖性磷脂酶A2(Pla2G6)编码组。我们以前的研究表明，人的Pla2g6同时水解磷脂和溶血磷脂产生游离脂肪酸，而与疾病相关的突变极大地削弱了蛋白质的催化活性。这预示着INAD/NBIA中有两条潜在的病理途径：Pla2G6底物(磷脂)的积聚和Pla2G6产物(游离脂肪酸)的缺乏。之前对细胞系的研究也支持Pla2g6在磷脂和脂肪酸动态平衡中的作用。Pla2g6底物的积累解释了人类疾病的一个特征--在称为神经轴突球的病理结构中膜的积累。我们之前报道的Pla2G6-KO小鼠模型概括了神经轴突球体的形成以及人类疾病的进行性神经损害。我们将使用Pla2g6-KO小鼠来测试一种治疗方法，以提高脂肪酸合成和摄取的速度，以补偿由Pla2g6突变导致的脂肪酸释放受损。这种方法将利用一种小分子肝X受体(LXR)激动剂。LXR是固醇调节元件结合蛋白1c(SREBP-1c)表达的核受体转录激活物，也直接激活参与脂肪酸合成和摄取的蛋白质的表达。LXR激动剂将用于Pla2g6-KO和野生型小鼠。将评估LXR激动剂对脑组织脂肪生成基因表达、脂肪酸合成和脂肪酸摄取的影响。LXR激动剂对进行性神经损害的效果将通过旋转棒试验和其他感觉运动功能的行为测试以及脑组织的组织病理学分析来评估。这些研究中的积极结果可以通过利用LXR激动剂在人类身上转化为新的治疗方法，目前正在开发的LXR激动剂在调节其他疾病的脂代谢方面具有潜在的治疗效果。

DESCRIPTION (provided by applicant): Mutations in the PLA2G6 gene cause young onset neurodegenerative disorders classified as either infantile neuroaxonal dystrophy (INAD) or neurodegeneration with brain iron accumulation (NBIA). These two disorders with overlapping features involve progressive impairment of movement, speech and cognition. The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 (Pla2g6). Our previous studies indicate that human Pla2g6 hydrolyzes both phospholipids and lysophospholipids to produce free fatty acids, and that disease-associated mutations dramatically impair the catalytic activity of the protein. This predicts two potential pathological pathways in INAD/NBIA: accumulation of Pla2g6 substrates (phospholipids) and deficiency of Pla2g6 products (free fatty acids). Previous studies in cell lines also support a role for Pla2g6 in phospholipid and fatty acid homeostasis. Accumulation of Pla2g6 substrates explains a characteristic feature of the human disease - accumulation of membranes in pathological structures termed neuroaxonal spheroids. Our previously reported Pla2g6-KO mouse model recapitulates neuroaxonal spheroid formation as well as progressive neurological impairment of the human disorder. We will use Pla2g6-KO mice to test a therapeutic approach to increase the rate of fatty acid synthesis and uptake in order to compensate for impaired release of fatty acids caused by Pla2g6 mutations. This approach will utilize a small molecule liver X receptor (LXR) agonist. LXR's are nuclear receptor transcriptional activators of sterol regulatory element binding protein 1c (SREBP-1c) expression and also directly activate the expression of proteins involved in fatty acid synthesis and uptake. The LXR agonist will be administered to Pla2g6-KO and wildtype mice. The effect of the LXR agonist on lipogenic gene expression, fatty acid synthesis, and fatty acid uptake in brain tissue will be evaluated. The effect of the LXR agonist on progressive neurological impairment will be evaluated using the rotarod test and other behavioral tests of sensorimotor function, and by histopathological analysis of brain tissue. Positive results in these studies could be translated into new therapeutic approaches in humans by utilizing LXR agonists which are currently being developed for potential therapeutic effects in regulating lipid metabolism in other disorders.