Editors' ChoiceNeurology

Energy Hunting(tin)

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Science Translational Medicine  06 Mar 2013:
Vol. 5, Issue 175, pp. 175ec40
DOI: 10.1126/scitranslmed.3006038

Neurons are critically dependent on energy: Just 10 minutes without a blood supply to the brain is enough to damage human neurons. One reason neurons need constant energy is to support their axons, the long-distance connections to other neurons that propagate the brain’s electric and humoral signals. Now, Zada et al. have discovered that glycolysis serves as an auxiliary source of energy within axons and that huntingtin, the protein that is mutated in Huntington’s disease, is an essential part of this glycolytic machinery.

Because some axons can be as long as 1 meter—a cosmic distance in cellular terms—axonal function is supported by a highly complex, fast axonal transport system. Vesicles rapidly move essential cargo such as trophic factors and neurotransmitters along the microtubule tracks. Operation of this lengthy transport route requires large amounts of adenosine 5´-triphosphate (ATP), a molecular ordinarily made by oxidative phosphorylation in mitochondria. But in axons, the authors demonstrate, mitochondria are not up to the task, and the power for fast axonal transport actually comes from a less-efficient (yet abundant) auxiliary ATP-producing system: the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This enzyme augments the ATP supply through local glycolysis within the axon itself. GAPDH is omnipresent around the axonal motor proteins dynein and kinesin and provides their main source of energy for moving vesicles.

To keep GAPDH handy, the fast-moving vesicles use the protein huntingtin as a scaffold that localizes GAPDH to the vesicles. This central role of huntingtin in axonal energy metabolism may explain the axonal transport defect seen in neurons with the mutant form of huntingtin, a possible contribution to the disease. A futuristic application of this impressively elegant study could include artificially designed scaffolds that substitute for defective huntingtin and allow neurons to thrive and happily connect in patients with Huntington’s disease.

D. Zala et al., Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152, 479–491 (2013). [Abstract]

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