Role of FABP7 in ALS models

摘要 这项提案的目标是确定减少脂肪酸结合蛋白7(FABP7) 表达改善肌萎缩侧索硬化症(ALS)模型中运动神经元的变性。FABP 属于一个小分子(~15 kDa)家族，广泛表达于细胞内。所有FABP都表现出很高的亲和力 饱和和不饱和长链脂肪酸以及其他脂类的可逆结合。FABP一直是 被认为是生物上沉默的脂肪酸伴侣，但现在已经清楚的是，FABP是核心 调节脂肪代谢、能量平衡和炎症。FABP参与脂肪酸 代谢调节它们的摄取和运输，但也可以通过分布来调节信号过程 和/或隔离核受体的配体，如过氧化物酶体增殖物激活受体 (PPAR)。FABP7(也称为脑脂结合蛋白，BLBP)在神经干细胞中表达 在整个发育过程中，其表达减少，并局限于星形胶质细胞和放射状细胞 成人中枢神经系统中的神经胶质细胞。反应性星形胶质细胞上调FABP7在多发性硬化中的表达 病理情况。为了有效地运输和捐赠结合的配体，FABP在同一分子中表现出亲和力 范围或略弱于PPAR显示的范围。然而，上调FABP的表达可以 产生一种“汇效应”，负面调节PPAR的内源性配体的可用性(即，增加 细胞内FABP水平将导致PPAR活性降低)。PPAR控制以下内容的表达 参与协调细胞内代谢和炎症途径的基因。因此，PPAR降低 活动可导致脂质介导的信号转导和核因子-kB激活，这是ALS的两个显著特征。 星形胶质细胞。我们的数据首次显示，FABP7的上调可能是导致这种下降的原因 ALS星形胶质细胞PPAR活性及伴随的核因子-kB活性增加。利用细胞培养和小鼠 我们将评估FABP7表达减少应恢复正常活动的假设 这两个相互连接的网络可以潜在地提供对星形胶质细胞介导的运动的保护 ALS模型中的神经元死亡。

Abstract The goal of this proposal is to establish whether decreasing fatty acid-binding protein 7 (FABP7) expression ameliorates motor neuron degeneration in amyotrophic lateral sclerosis (ALS) models. The FABPs belong to a family of small (~15kDa) and widely expressed intracellular proteins. All FABPs exhibit high affinity reversible binding of saturated and unsaturated long-chain fatty acids as well as other lipids. FABPs have been considered biologically silent chaperones of fatty acids, but it has now become clear that the FABPs are central regulators of lipid metabolism, energy homeostasis and inflammation. FABPs participate in fatty acid metabolism regulating their uptake and transport but can also regulate signaling processes by distributing and/or sequestering ligands for nuclear receptors such as peroxisome proliferator activated receptors (PPARs). FABP7 (also known as brain lipid binding protein, BLBP) is expressed in neural stem cells throughout development and its expression decreases and becomes restricted to astrocytes and radial-like glial cells in the adult central nervous system. Reactive astrocytes up-regulate FABP7 expression in multiple pathological conditions. To effectively transport and donate bound ligands, FABPs display affinities in the same range or slightly weaker than those exhibited by PPARs. However, up-regulation of FABPs expression can create a “sink effect”, negatively regulating the availability of endogenous ligands for PPARs (i.e., increased intracellular levels of FABPs will result in decreased PPARs activation). PPARs govern the expression of genes involved in coordinating metabolic and inflammatory pathways in the cell. Thus, decreased PPAR activity can contribute to altered lipid-mediated signaling and NF-kB activation, two prominent features of ALS- astrocytes. Our data show for the first time that FABP7 up-regulation may be responsible for the decreased PPAR activity and concomitant increase in NF-kB activity in ALS-astrocytes. Using cell culture and mouse models we will evaluate the hypothesis that decreasing FABP7 expression should restore normal activity of these two interconnected networks and can potentially provide protection against astrocyte-mediated motor neuron death in ALS models.