Signaling from neighboring cells provides power boost within axons

"Many major neurological disorders involve the degeneration of axons, mitochondrial dysfunction, decreased energy levels, or problems with oligodendrocytes," said Zu-Hang Sheng, Ph.D., senior investigator at NINDS. "Our findings uncover a way for axons to maintain energy and could help us better understand the causes of neurological disorders and how we might treat them."

All cells including neurons use adenosine triphosphate (ATP) for fuel, which is created by structures within cells called mitochondria. The NINDS research team led by Dr. Sheng discovered that oligodendrocytes -- cells that typically support axons by wrapping them in an insulating material called myelin -- release an enzyme, SIRT2, that ramps up mitochondrial activity. This enzyme, when picked up by axons, provides a local power boost by increasing energy production.

"Neurons require considerable amounts of ATP for energy, but ATP has a hard time traveling down long axons," said Dr. Sheng. "We wanted to understand how neurons can keep energy levels high inches, or even sometimes feet, all the way along the axon."

Like regional power plants built to provide electricity to remote locations, mitochondria are located along long axons to generate ATP in areas where it is needed. Previous studies showed that axons that have had myelin removed contain more mitochondria, while genetic changes that affect oligodendrocytes also impact energy production in axons.

Using a state-of-the-art energy sensor that changes color based on local ATP availability, Dr. Sheng's team compared energy levels in neurons and their axons grown in cell dishes with or without oligodendrocytes. What they saw was that the axons grown with oligodendrocytes had significantly more ATP than those without, suggesting there was some connection between the support cells and the levels of energy in axons.

Next, Dr. Sheng and his colleagues created "conditioned media" by growing oligodendrocytes in lab dishes for several days and then collecting media but not the cells. The conditioned media was then added to dishes containing neurons, and this treatment also increased ATP levels, which meant that oligodendrocytes were releasing cellular components into their environment that ramped up energy production in axons.

The question remained: what was being released by the oligodendrocytes? To answer this, Drs. Chamberlain and Huang, two leading authors of the study, and their collaborators isolated exosomes -- packages released from cells that contain signaling molecules -- from oligodendrocytes and showed that they too can increase energy production in axons. Taking advantage of a previous study that identified many components within exosomes, the researchers focused on a protein called SIRT2 and confirmed that it is present at high levels in oligodendrocytes, but not neurons.

SIRT2 also made an intriguing target because it is an enzyme that modifies proteins, including those in mitochondria and specifically those linked to ATP production. When the researchers genetically turned on SIRT2 in neurons, they saw significantly higher ATP levels. In contrast, when neurons were grown with oligodendrocytes missing the gene for SIRT2, no increase in energy was seen. Finally, when SIRT2-containing exosomes were added to the spinal cords of mice lacking the gene for SIRT2, there was a strong increase in mitochondrial function. Together, these findings suggest oligodendrocytes help axons maintain high levels of energy when needed.

Several neurodegenerative diseases, including ALS, have been linked to a failure of mitochondria to produce sufficient energy in neurons and their axons. The discovery of SIRT2 as a transcellular signal that can boost energy production locally within axons means that this pathway could be a potential target for future therapies for certain neurodegenerative disorders.

This study was supported by the Intramural Research Program at NINDS.