Insulin signaling mediates neurodegeneration in glioma

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how the glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue the synapse loss and to delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies. Significance StatementGlioblastoma (GB) is the most aggressive type of brain tumour and currently there is no cure or effective treatment. Patients course with neurological decay and previous data in animal models indicate that GB cause a neurodegenerative process. We describe here a molecule named ImpL2 that is produced by GB cells and impact on neighbouring neurons. ImpL2 is an antagonist of the insulin pathway and signaling reduction in neurons causes mitochondrial defects and synapse loss. These mechanisms underlying GB-induced neurodegeneration plays a central role in the premature death caused by this tumour. Restoration of insulin signaling in neurons prevents tumour progression and rescues the lethality caused by GB in Drosophila models.