Final Report Summary - MITONEUROMAGE (The role of MAGE proteins in mitochondria: Novel insights for the regulation of neuronal function)
1. Executive summary
Diseases that entail metabolic dysfunction are becoming epidemic in modern societies. They not only compromise the quality of life, but also constitute a great socio-economic burden. Moreover, it is becoming increasingly apparent that metabolic dysfunction is not merely responsible for diseases such as diabetes and heart disease, but also for a wide range of neurological disorders. These include age-related neurodegenerative diseases, as well as disorders with developmental origin such as autism spectrum disorders, schizophrenia and other syndromes that entail compromised cognitive function and intellectual disability.
Prader-Willi is one such syndrome that is caused by deletion of two genes, encoding for proteins of the Melanoma antigen (MAGE) superfamily, Necdin and MAGEL2. Manifested already at birth, patients display aberrant cognitive function and psychoses, while at the same time they suffer from hyperphagia, high body fat mass and obesity that is often morbid and accounts for their reduced lifespan. The precise function of Necdin and MAGEL2 in neurons remained elusive, although the symptoms associated with their genetic ablation clearly pointed to a role in neuronal metabolism. As mammals contain a large number of MAGE proteins, analysing the role of individual members is not an easy task.
To circumvent this complication, we took advantage of the nematode C. elegans, a powerful genetic model that contains only one MAGE protein, which we cloned and named MAGE-1. We found that MAGE-1 is expressed in neurons and localizes primarily to mitochondria. Our findings indicate that loss of MAGE-1 leads to mitochondrial fragmentation, induction of autophagy and accumulation of body fat. Mechanistically, we found that MAGE-1 regulates the activity of SKN-1, a master regulator of mitochondrial biogenesis. At the organismal level, MAGE-1-deficiency resulted in increased resistance to oxidative stress.
Importantly, these findings have predictive value for the role of the mammalian orthologue, Necdin, in neurons. In line with the nematode findings, we verified that Necdin is partially localized to mitochondria where it interacts with specific components of the electron transport chain. Taken together, our findings reveal a novel, evolutionarily conserved function of Necdin in the regulation of mitochondrial maintenance and autophagy, two processes that are critical for the overall homeostasis of neurons. Therefore, this work has contributed to the European effort to improve the health of European citizens by addressing global health issues, as well as to European competitiveness, thus meeting the objectives of health research.
Diseases that entail metabolic dysfunction are becoming epidemic in modern societies. They not only compromise the quality of life, but also constitute a great socio-economic burden. Moreover, it is becoming increasingly apparent that metabolic dysfunction is not merely responsible for diseases such as diabetes and heart disease, but also for a wide range of neurological disorders. These include age-related neurodegenerative diseases, as well as disorders with developmental origin such as autism spectrum disorders, schizophrenia and other syndromes that entail compromised cognitive function and intellectual disability.
Prader-Willi is one such syndrome that is caused by deletion of two genes, encoding for proteins of the Melanoma antigen (MAGE) superfamily, Necdin and MAGEL2. Manifested already at birth, patients display aberrant cognitive function and psychoses, while at the same time they suffer from hyperphagia, high body fat mass and obesity that is often morbid and accounts for their reduced lifespan. The precise function of Necdin and MAGEL2 in neurons remained elusive, although the symptoms associated with their genetic ablation clearly pointed to a role in neuronal metabolism. As mammals contain a large number of MAGE proteins, analysing the role of individual members is not an easy task.
To circumvent this complication, we took advantage of the nematode C. elegans, a powerful genetic model that contains only one MAGE protein, which we cloned and named MAGE-1. We found that MAGE-1 is expressed in neurons and localizes primarily to mitochondria. Our findings indicate that loss of MAGE-1 leads to mitochondrial fragmentation, induction of autophagy and accumulation of body fat. Mechanistically, we found that MAGE-1 regulates the activity of SKN-1, a master regulator of mitochondrial biogenesis. At the organismal level, MAGE-1-deficiency resulted in increased resistance to oxidative stress.
Importantly, these findings have predictive value for the role of the mammalian orthologue, Necdin, in neurons. In line with the nematode findings, we verified that Necdin is partially localized to mitochondria where it interacts with specific components of the electron transport chain. Taken together, our findings reveal a novel, evolutionarily conserved function of Necdin in the regulation of mitochondrial maintenance and autophagy, two processes that are critical for the overall homeostasis of neurons. Therefore, this work has contributed to the European effort to improve the health of European citizens by addressing global health issues, as well as to European competitiveness, thus meeting the objectives of health research.