Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration

Living cells need to maintain an optimal balance between making new proteins and destroying older ones. Building proteins requires a supply of nutrients and appropriate levels of energy, and mammalian cells rely on a protein called mTOR to sense both nutrient availability and energy levels. Nutrients activate mTOR signaling to promote protein synthesis. In contrast, a lack of nutrients and low energy levels inhibit mTOR, which slows down protein synthesis to help the cell to conserve vital resources. The balance between protein synthesis and degradation is often perturbed in diseases that involve the progressive loss of nerve cells, and a drug called rapamycin – which inhibits mTOR signalling – can help treat this neurodegeneration in mice. Neurodegenerative diseases are also often linked to problems with the cellular structures called mitochondria that provide the cell with energy in the form of the chemical ATP. Previous research suggests that abnormal mitochondrial activity and energy deficiency could be a critical step that leads to neuron death in neurodegeneration. So far, the effect of rapamycin on energy deficiency in neurons has not been explored in detail. Zheng, Boyer et al. have now tested the therapeutic potential of rapamycin in a genetic disease called maternally inherited Leigh syndrome in which children suffer from severe neurodegeneration due to defects in their mitochondria. The experiments made use of neurons that could be grown in the laboratory and which faithfully mimicked the problems observed in maternally inherited Leigh syndrome patients. In some experiments, healthy neurons were treated with chemicals that inhibit ATP production. In other experiments, cells collected from a maternally inherited Leigh syndrome patient were coaxed into becoming neurons. Signaling via mTOR was enhanced in both kinds of neurons. Zheng, Boyer et al. then treated the defective neurons with rapamycin, which led to a significant rise in ATP levels. The production of proteins also slowed down. This could explain the observed rise in ATP levels, as making proteins consumes a lot of energy. Zheng, Boyer et al. propose that a mild reduction in protein synthesis may have the potential to treat neurodegeneration caused by defective mitochondria. Further work is needed to extend this analysis to animal models of neurodegenerative diseases.