09:01am Monday 13 July 2020

Redefining the Brain's Energy Grid

Using a glowing firefly protein, Dr. Timothy Ryan and his team can monitor and measure the energy molecule ATP in nerve cells and at the sites of contact where they communicate, synapses. In their study in Cell, they show that ATP at synapses is produced on demand, rather than continuously. The finding suggests that brain disorders may be caused by mutations or malfunctions in this on-demand circuitry. Illustration by Evan J. Molinelli and Vidhya Rangaraju

But, as a team of researchers at Weill Cornell Medical College report in the Feb. 13 issue of Cell, energy is produced on an as-needed basis at the end of the nerve that releases neurotransmitters — the all-important presynaptic side of brain cells. Power production flips on when one neuron needs to communicate with another.

The difference likely means that brain disorders are caused by mutations or malfunctions in the on-demand circuitry of the organ’s power supply, which then causes communication glitches between cells, says the study’s senior researcher, Dr. Timothy Ryan, a professor of biochemistry. While it’s not yet clear why these ATP deficits occur, the finding suggests new therapeutic approaches investigators might take against neurogenerative disorders.

“This finding challenges our understanding of neurodegenerative diseases,” Dr. Ryan says. “The most important thing the brain does is communicate. This study suggests that the root of some disorders — if not all — may be the inability of neurons to make ATP on demand.”

So, instead of, say, turning on a lamp with a switch that just taps into an ever-ready source of household electricity, it is as if the lamp, when switched on, makes its own energy on the spot to produce light, he says.

“No one knew, before this research, that ATP is being made on demand, in response to neurotransmitter activity, in the presynaptic neuron,” Dr. Ryan says. “If the power is not there, neurotransmission fails. And the inability to send neurotransmitters across the synapse leads to disease.

“Once we define the molecular pathways that regulate this system, we can look for malfunctions that lead to energy imbalances that hamper neurotransmission — and possibly target them with new therapies.”

The discovery was made possible by a unique technology that Dr. Ryan and his team invented.

They used a firefly protein that glows to create molecules that can bind to ATP chemicals at the neuronal synapse. The degree of brightness in the luminescent protein indicates levels of ATP at the presynaptic gap. “We can literally see how the brain is powered,” Dr. Ryan says.

He and his Weill Cornell colleagues, Vidhya Rangaraju, a chemical biology graduate student, and biochemist Dr. Nathaniel Calloway, then conducted a series of experiments. They first estimated that there are typically about 1 million molecules of ATP at each neuronal synapse. The researchers then cut off the supply of ATP and found that all of those molecules dissipate in about 2 minutes.

They then looked at what happens to ATP when neurons release neurotransmitters and when they are not active. When they blocked neurotransmission, ATP decayed much more slowly. If they coaxed a neuron to become very active, ATP levels remained high. These experiments and others revealed that presynaptic activity tells the neuron to make ATP and that when there is no activity, there is no need to make fuel.

“This is very different from the common dogma that neurons make a ton of ATP all the time in case neurotransmission is needed,” Dr. Ryan says. “The machinery to make ATP has been known for a long time, but we just didn’t realize that something else was in command, telling the machines when to work.

“We are now on the hunt for that something else because we believe it might be a player in brain disease,” he says.

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