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Metabolism and apoptosis crosstalk in the brain

Increasing life expectancy has brought with it a corresponding rise in the prevalence of neurodegenerative disorders. Considering the energy requirements of the brain, European scientists investigated the association between metabolic dysfunction and neuronal cell death.
Metabolism and apoptosis crosstalk in the brain
Neurodegenerative diseases are classically not considered to be caused by disturbed metabolism. However, emerging evidence points towards bioenergetic defects as important pathophysiological mechanisms. Neurons – unlike most other cell types – preferably rely on glucose to function and are particularly intolerant to inadequate energy supply. An acutely or chronically disturbed metabolic environment such as after stroke or hypoxia causes oxidative stress and neuronal cell death, leading to degeneration.

Several glucose-metabolising enzymes are involved in regulating cell survival in neurons, including the mitochondrial glucose-phosphorylating enzyme hexokinase II (HKII). HKII functions as a molecular switch regulating neuronal survival depending on the metabolic state. However, the molecular mechanism by which these protein to protein interactions are regulated remain elusive.

Scientists of the EU-funded AINIGMA (Analysing intravital neuronal protein interactions in metabolism and apoptosis) project were interested in characterising the intersection among cell death pathways in the brain with pathways regulating metabolism. In particular, they studied these events in stroke and addressed how metabolism regulates neuronal degeneration.

Researchers generated expression systems to investigate the interaction among different proteins and their metabolic impact under different conditions. In addition, they combined protein interaction studies in live induced pluripotent stem (iPS) cell-derived human neurons with novel biophysical tools such as fluorescence lifetime imaging microscopy and high throughput live cell RNA interference (RNAi) screens. Their activities focused on specific molecular events in neuronal cell death regulation.

Overall, the findings of the project provided fundamental insight into physiological and pathophysiological brain function and highlighted the role of metabolism in neuronal cell survival.

AINIGMA has unveiled novel avenues for therapy or prevention of neurodegenerative diseases based on metabolic manipulation. Importantly, these findings extend beyond stroke in other neurodegenerative diseases such as Alzheimer’s disease.

Related information

Subjects

Life Sciences

Keywords

Metabolism, neurodegenerative, neuron, hexokinase, AINIGMA
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