Astroglial Monocarboxylate Transporter (MCT) Pathway in Neurodegeneration

描述(申请人提供)：越来越多的证据表明，星形胶质细胞是支持正常神经元功能的关键，而星形胶质细胞功能障碍可能导致一些神经退行性疾病。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。大部分营养支持是以葡萄糖的形式提供的；然而，理论上认为，另一种途径，包括乳酸，也可能是神经元的重要能量来源。星形胶质细胞通过糖酵解产生大量乳酸，乳酸可以通过星形胶质细胞中的MCT1、MCT4和神经元上的MCT2等不同的分子亚种被转运到神经元。最近的活体研究表明，兴奋性传递可能在一定程度上受到星形胶质细胞对神经元代谢的网络调控。在体外，外源性乳酸或与星形胶质细胞共培养均可防止缺糖诱导的神经细胞死亡。星形胶质细胞的这种保护功能被星形胶质乳酸转运蛋白MCT1和MCT4的抑制剂处理而丧失。在这项建议中，我们将首先确定MCT1或MCT4输出的星形胶质细胞乳酸对于神经元在体外存活是必要的。这些研究将检验星形胶质乳酸输出是神经元的基本星形胶质支持途径的假设。然后我们将确定星形胶质乳酸转运体MCT1/MCT4是否是A)体内正常神经元功能/活动的参与者，以及B)体内神经元存活所必需的。我们假设星形胶质细胞的MCT转运蛋白可能是正常神经元功能所必需的。最后，我们将确定MCT表达的失调是否有助于ALS模型的神经退变，以及这一途径的修复是否具有神经保护作用。总体而言，我们假设星形胶质细胞通过星形胶质细胞特异性转运蛋白MCT1/MCT4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，并在ALS等疾病中导致运动神经元死亡。

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.