Astroglial Monocarboxylate Transporter (MCT) Pathway in Neurodegeneration

描述（由申请人提供）：越来越多的证据表明星形胶质细胞对支持正常神经元功能至关重要，星形胶质细胞功能障碍可能导致许多神经退行性疾病。星形胶质细胞的一个重要功能是将营养物质从毛细血管输送到神经元。大部分的营养支持是以葡萄糖的形式存在的；然而，从理论上讲，另一种途径，包括乳酸，也可能是神经元能量的重要来源。星形胶质细胞通过糖酵解产生大量乳酸，乳酸可以通过不同的分子亚种——星形胶质细胞中的MCT1、MCT4和神经元上的MCT2——从星形胶质细胞转运到神经元。最近的体内研究表明，兴奋性传递可能部分通过星形胶质细胞对神经元代谢的网络调节来调节。在体外，外源性乳酸或与星形胶质细胞共培养能够预防葡萄糖剥夺引起的神经元细胞死亡。星形胶质细胞的这种保护功能在星形胶质乳酸转运体MCT1和MCT4抑制剂治疗后丧失。在本提案中，我们将首先确定MCT1或MCT4的星形胶质乳酸输出是否对体外神经元存活是必要的。这些研究将验证星形胶质细胞乳酸输出是神经元的基本星形胶质细胞支持途径的假设。然后，我们将确定星形胶质乳酸转运体MCT1/MCT4是否A)参与体内正常神经元功能/活动，B)在体内神经元存活所必需。我们假设星形胶质MCT转运体可能是正常神经元功能所必需的。最后，我们将确定MCT表达失调是否导致ALS模型中的神经退行性变，如果该通路的修复具有神经保护作用。总的来说，我们假设星形胶质细胞通过星形胶质细胞特异性转运体MCT1/MCT4转运/输出必需乳酸来支持神经元，这一途径是神经退行性变中星形胶质细胞功能障碍的重要组成部分，并导致ALS等疾病中的运动神经元死亡。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that astrocytes are critical for the support of normal neuronal function, and astrocyte dysfunction may contribute to a number of neurodegenerative diseases. One important function of astrocytes is to transport nutrients from capillaries to neurons. Much of the nutritional support is in the form of glucose; however, it has been theorized that an alternate pathway, involving lactate, may also be an important source of energy for neurons. Astrocytes produce high amounts of lactate through glycolysis, and lactate can be transported from astrocytes to neurons via distinct molecular subspecies- MCT1, MCT4 in astroglia and MCT2 on neurons. Recent in vivo studies suggest that excitatory transmission may be regulated- in part - by networked astrocyte regulation of neuronal metabolism. In vitro, exogenous lactate or co-culturing with astrocytes is able to prevent the neuronal cell death induced by glucose deprivation. This protective function of astrocytes is lost by treatment with inhibitors to astroglial lactate transporters MCT1 and MCT4. In this Proposal we will first determine if astroglial lactate export by MCT1 or MCT4 is necessary for neuronal survival in vitro. These studies will test the hypothesis that astroglial lactate export is a fundamental astroglial support pathway for neurons. We will then determine if astroglial lactate transporters MCT1/MCT4 are A) Participants in normal neuronal function/activity in vivo and B) are necessary for neuronal survival in vivo. We hypothesize that Astroglial MCT transporters are likely to be necessary for normal neuronal function. Finally we will determine if dysregulation of MCT expression contributes to the neurodegeneration in ALS models if and repair of this pathway is neuroprotective. Overall, we hypothesize that astrocytes support neurons via essential lactate transport/export thru astrocyte specific transporters MCT1/MCT4 and that this pathway is a significant part of astroglial dysfunction in neurodegeneration and contributes to motor neuron death in diseases like ALS.