Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

Abstract

Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.

Figure 1

Schematic overview of the astrocyte-neuron metabolic coupling gene set, showing genes positively contributing to the gene-set association with Tourette syndrome. Genetic alterations in astrocyte-neuron metabolic coupling may have downstream effects on various neuronal energy metabolism processes, particularly at synapses: (1) glycolysis-dependent lactate release to the synapse where it is used for ATP generation and (2) glutamate (or GABA) uptake from the synaptic cleft by astrocytes where one part is converted to glutamine and returned to neurons for conversion back to glutamate (or GABA), and another part is used for production of pyruvate and lactate. See main text for further explanation.