Neurons use built-in ‘backup batteries’ that fuel the brain under stress with glycogen

Amazing stuff!

"... describe how neurons store their own glycogen, a form of sugar that helps neurons stay resilient when their main energy sources falter. 

The findings illustrate how neuron cells can adapt their metabolism, researchers say, and could shape new treatments for neurological conditions like stroke, neurodegeneration, and epilepsy, all disorders in which energy failure plays a role. ...

A breakthrough came when researchers discovered the enzyme PYGL-1, the worm’s version of the human glycogen phosphorylase enzyme that converts glycogen into fuel for neurons. When researchers removed PYGL-1, the worm neurons could no longer ramp up energy during low-oxygen stress conditions; when the enzyme was specifically restored in neurons, that failure was reversed.

“We discovered that neurons use two different strategies to adapt to energy stress: one that’s glycogen-dependent, and one that isn’t,”  ... “The glycogen-dependent pathway is particularly critical when the mitochondria — one of the cell’s primary energy producers — aren’t functioning well. In those situations, glycogen serves as a backup system to provide energy via glycolysis.” ..."

From the significance and abstract:

"Significance

It has long been assumed that glycogen in the brain is primarily a glial energy reserve, with limited direct relevance to neurons. Yet, recent studies have demonstrated a role for glycogen in neuronal function. Here, we extend these findings, demonstrating that neurons directly metabolize glycogen to support glycolysis in vivo. Using a metabolic biosensor in Caenorhabditis elegans, we uncover a neuron-intrinsic, glycogen-dependent glycolytic plasticity that is specifically activated during hypoxia and mitochondrial dysfunction. This direct neuronal use of glycogen is essential for sustaining synaptic function, revealing an unexpected and critical role for glycogen in neuronal energy metabolism.

Abstract

Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood.

We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia.

We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity.

We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity.

We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function."

Neurons use built-in ‘backup batteries’ that fuel the brain under stress | Yale News "A new Yale study reveals that neurons store their own sugar reserves that kick in to keep the brain functioning during metabolic stress."

Glycogen supports glycolytic plasticity in neurons (open access)

Fig. 4 pygl-1/Glycogen phosphorylase is required for glycolytic plasticity and synaptic vesicle recycling during mitochondrial impairment.