Involvement of monocarboxylate transporters in neurodegenerative diseases
Monocarboxylate transporters (MCTs) catalyze the proton linked transport of monocarboxylates like lactate across plasma membranes. Lactate is generated from glucose and metabolized by eg neurons for the production of ATP. In the CNS MCT1 transporters are expressed by oligodendrocytes and some specific neuronal subpopulations in the brain, whereas neurons generally express MCT2 transporters. Oligodendrocytes are well known not only to support transmission of action potentials by myelination of axons, but also exerting trophic support through eg lactate release independent of myelination. In our laboratory it has previously been found that impairment of lactate transport through MCT1 specifically in oligodendrocytes leads to extensive axonal degeneration. These data indicate that neurons depend on the continuous influx and metabolism of lactate released by oligodendrocytes in order to maintain their physiological homeostasis. Also, in CNS tissue of patients with the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) as well as in ALS mouse models, a significant reduction in the expression levels of MCT1 transporters was found, suggesting that oligodendrocyte mediated trophic support of motor neurons is impaired. The main aim of this study is to further explore the role of MCT1 transporters in models of neurodegeneration. We are exploring the basic biology of MCT1 transporters as oligodendrocytes mature from oligodendrocyte progenitor cells under normal physiological conditions as well as in disease models, eg mouse models for ALS. In addition, using viral vector mediated approaches as well as transgenic animal models, we are exploring whether enhancing or depleting MCT1 mediated trophic support in oligodendrocytes affects neurodegeneration in the models under study.
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