THERAPEUTIC APPROACHES FOR NEURODEGENERATION CAUSED BY PLA2G6 MUTATIONS

描述（由申请人提供）：PLA 2G 6基因突变引起幼年型神经退行性疾病，分类为婴儿神经轴索营养不良（INAD）或伴有脑铁蓄积的神经退行性疾病（NBIA）。这两种具有重叠特征的疾病涉及运动、言语和认知的进行性损害。PLA 2G 6基因编码VIA族钙非依赖性磷脂酶A2（Pla 2g 6）。我们以前的研究表明，人Pla 2g 6水解磷脂和溶血磷脂产生游离脂肪酸，疾病相关的突变显着损害蛋白质的催化活性。这预测了INAD/NBIA中的两种潜在病理途径：Pla 2g 6底物（磷脂）的积累和Pla 2g 6产物（游离脂肪酸）的缺乏。先前在细胞系中的研究也支持Pla 2g 6在磷脂和脂肪酸稳态中的作用。Pla 2g 6底物的积累解释了人类疾病的特征-在称为神经轴突球体的病理结构中膜的积累。我们先前报道的Pla 2g 6-KO小鼠模型重现了神经轴突球体形成以及人类疾病的进行性神经功能缺损。我们将使用Pla 2g 6-KO小鼠来测试增加脂肪酸合成和摄取速率的治疗方法，以补偿Pla 2g 6突变引起的脂肪酸释放受损。该方法将利用小分子肝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剂，并且还直接激活参与脂肪酸合成和摄取的蛋白质的表达。将LXR激动剂给予Pla 2g 6-KO和野生型小鼠。将评价LXR激动剂对脑组织中脂肪生成基因表达、脂肪酸合成和脂肪酸摄取的影响。将使用旋转棒试验和感觉运动功能的其他行为试验以及通过脑组织的组织病理学分析来评价LXR激动剂对进行性神经损伤的影响。这些研究中的积极结果可以通过利用LXR激动剂转化为人类的新治疗方法，目前正在开发LXR激动剂，用于调节其他疾病中的脂质代谢的潜在治疗效果。 公共卫生相关性：该项目将在小鼠模型中测试一种新的治疗方法，用于治疗由PLA 2G 6基因突变引起的人类神经退行性疾病。这些研究的结果将提高对疾病机制的理解，并指导治疗婴儿神经轴索营养不良和脑铁积累神经变性等人类疾病的发展。

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. PUBLIC HEALTH RELEVANCE: This project will test a novel therapeutic approach in a mouse model for a human neurodegenerative disorder caused by mutations in the PLA2G6 gene. Results from these studies will improve the understanding of disease mechanisms and guide the development of treatments for the human disorders known as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.