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The molecular determinants of neuronal metabolic dysfunction

European researchers investigated how the melanoma antigen (MAGE) genes cause metabolic dysfunction in neurons.
The molecular determinants of neuronal metabolic dysfunction
MAGE genes have received increasing attention due to their roles in human diseases, mainly cancer and neurodevelopmental disorders. Two members of the MAGE superfamily, necdin and MAGEL2, cause the Prader-Willi syndrome. This genetic disorder is associated with aberrant cognitive function and psychoses, as well metabolic dysfunctions such as hyperphagia, high body fat mass and obesity.

Scientists on the EU-funded MITONEUROMAGE (The role of MAGE proteins in mitochondria: Novel insights for the regulation of neuronal function) project wished to investigate the precise function of necdin and MAGEL2 in neuronal metabolism. Given the large number of MAGE proteins in mammals, they employed as a model the nematode Caenorhabditis elegans that contains only one MAGE protein.

Project results indicated that MAGE-1 was expressed in neurons and localised primarily to mitochondria. Researchers observed that loss of MAGE-1 led to mitochondrial fragmentation, induction of autophagy and accumulation of body fat.

Mechanistic insight into MAGE-1 function indicated that it regulated the activity of the master mitochondrial biogenesis regulator SKN-1. At the organism level, MAGE-1 deficiency resulted in increased resistance to oxidative stress. These findings were also verified in mammalian neurons, where scientists further showed that the mammalian orthologue necdin interacted with specific components of the electron transport chain.

Taken together, MITONEUROMAGE findings demonstrate an evolutionary conservation of necdin function in the regulation of mitochondrial maintenance and autophagy. Considering that these two processes are critical for the overall homeostasis of neurons, necdin implication provides a novel angle into neuronal disease pathology.

Related information

Keywords

Metabolic dysfunction, MAGE, neurons, necdin, MITONEUROMAGE
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