Astroglial Monocarboxylate Transporter (MCT) Pathway in Neurodegeneration

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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.