Signaling from neighboring cells provides power boost within axons


Date:
September 30, 2021
Source:
NIH/National Institute of Neurological Disorders and Stroke
Summary:
Nerve cells (neurons) send signals throughout the brain and the
body along long processes called axons; these communication and
information processes consume high levels of energy. A recent study
shows that the support cells around axons provide a way to boost
local energy production. The new findings help explain how long
axons maintain sufficient energy levels and could have implications
for the treatment of several neurological disorders, including
Parkinson's disease, Huntington's disease, and amyotrophic lateral
sclerosis (ALS), linked to disruptions in axonal energy supply.



FULL STORY ========================================================================== Nerve cells (neurons) send signals throughout the brain and the body
along long processes called axons; these communication and information processes consume high levels of energy. A recent study conducted at
the National Institute of Neurological Disorders and Stroke (NINDS),
part of the National Institutes of Health, shows that the support cells
around axons provide a way to boost local energy production. The new
findings, published in the journal Neuron, help explain how long axons
maintain sufficient energy levels and could have implications for the
treatment of several neurological disorders, including Parkinson's
disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS),
linked to disruptions in axonal energy supply.


========================================================================== "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.

========================================================================== Story Source: Materials provided by NIH/National_Institute_of_Neurological_Disorders_and Stroke. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kelly A. Chamberlain, Ning Huang, Yuxiang Xie, Francesca LiCausi,
Sunan
Li, Yan Li, Zu-Hang Sheng. Oligodendrocytes enhance axonal energy
metabolism by deacetylation of mitochondrial proteins through
transcellular delivery of SIRT2. Neuron, 2021; DOI: 10.1016/
j.neuron.2021.08.011 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210930140730.htm

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