LAUSR

Glutamatergic neurotransmission is essential for learning and memory but an overactivation of the pathway may lead to calcium overload, excitotoxicity and neuronal death. Together with this, oxidative stress and mitochondrial dysfunction are all relevant to the pathogenesis of neurodegenerative disorders such as frontotemporal dementia (FTD). Here, we have used fluorescence imaging techniques to study the interaction between those factors in iPSC-derived neurons from patients of FTD. FTD neurons showed a higher rate of mitochondrial ROS production and lipid peroxidation than the control cells. Enhanced oxidative stress led to increased cell death in the neurons of the patients, which could be prevented by treating them with mitochondrial antioxidants. Stimulation of the neurons with a physiological concentration of glutamate induced a higher and sustained elevation of the calcium levels in FTD neurons that was also prevented with mitochondrial antioxidants. Moreover, they were able to protect cells in a model of glutamate-induced excitotoxicity. These results show that mitochondrial ROS overproduction plays a central role in the glutamatergic signaling impairment and neurodegeneration in FTD, giving insight into new therapeutic strategies for the disease.