Fat particles could be key to treating metabolic brain disorders

For decades, it was widely accepted that neurons relied exclusively on glucose to fuel their functions in the brain. This is not the case.
Photo Credit: The University of Queensland

Scientific Frontline: Extended "At a Glance" Summary: Neuronal Lipid Metabolism

The Core Concept: Neurons, previously thought to rely entirely on glucose, actively utilize saturated free fatty acids produced by the DDHD2 gene to fuel their communication and functions.

Key Distinction/Mechanism: Rather than depending solely on sugars, healthy brain cells manufacture and consume small fat molecules for energy, and supplementing these fats can restore function when the natural metabolic pathways fail.

Origin/History: A 2025 University of Queensland study, led by Dr. Merja Joensuu, uncovered this mechanism while investigating the genetic basis of hereditary spastic paraplegia 54 (HSP54).

Major Frameworks/Components:

• The DDHD2 gene, which is responsible for regulating lipid balance and synthesizing necessary fatty acids.
• Saturated free fatty acids, which act as the alternative small fat molecules used for neuronal signaling.
• Hereditary spastic paraplegia 54 (HSP54), a debilitating metabolic disorder resulting from a loss of normal DDHD2 gene function.

Branch of Science: Neuroscience, Molecular Biology, Biomedical Science, and Neurobiology.

Future Application: The development of activated fatty acid supplements to treat HSP54 in clinical trials, alongside potential dietary or pharmaceutical therapies for Alzheimer's disease and other neurodegenerative conditions.

Why It Matters: This fundamental paradigm shift in understanding brain metabolism opens entirely new therapeutic pathways for repairing neuronal damage and restoring function in debilitating diseases that were previously deemed untreatable.

AIBN researcher Dr Merja Joensuu.
Photo Credit: The University of Queensland

Evidence challenging the long-held assumption that neuronal function in the brain is solely powered by sugars has given researchers new hope of treating debilitating brain disorders.

A University of Queensland study led by Dr Merja Joensuu showed that neurons also use fats for fuel as they fire off the signals for human thought and movement.

“For decades, it was widely accepted that neurons relied exclusively on glucose to fuel their functions in the brain,” Dr Joensuu said.

“But our research shows fats are undoubtedly a crucial part of the neuron’s energy metabolism in the brain and could be a key to repairing and restoring function when it breaks down.”

Dr Joensuu from the Australian Institute for Bioengineering and Nanotechnology along with lab members PhD candidate Nyakuoy Yak and Dr Saber Abd Elkader from UQ’s Queensland Brain Institute set out to examine the relationship of a particular gene (DDHD2) to hereditary spastic paraplegia 54 (HSP54).

Dr Joensuu said the loss of DDHD2 gene function was known to disturb the brain’s fat balance, which ultimately heralded the onset of HSP54.

“We discovered that neurons use small fat molecules, called saturated free fatty acids, produced by DDHD2 for energy to sustain neuronal communication,” Dr Joensuu said.

“Understanding the alternative brain fuel could help unlock new and more effective ways to treat energy-related brain disorders and neurodegenerative conditions.”

Dr Joensuu said the research laid the groundwork to develop a potential therapeutic for HSP54, and provides hope for other metabolic brain disorders and conditions previously thought untreatable.

We found that activated fatty acid supplements restored energy production and normal function even in neurons with the faulty DDHD2 gene in animal models, after an increase in sugars had proven ineffective,” Dr Joensuu said.   

PhD Scholar Nyakuoy Yak and Dr Merja Joensuu say their research could be the missing piece of the puzzle for a number of debilitating illnesses.
Photo Credit: The University of Queensland

“This was a huge paradigm shift. It showed that the healthy neurons in the brain produce saturated fatty acids that they use for fuel, and in conditions like HSP54, where this fatty acid energy pathway is faulty, the neuronal energy and damages could be repaired with fatty acid supplements.

“Given the brain’s metabolic vulnerability, and the metabolic changes in conditions like Alzheimer’s disease, this discovery could be the missing piece of the puzzle for a number of debilitating illnesses.”

Dr Joensuu said the next stage of the research is to assess the therapeutic efficacy and safety of the activated fatty acids in preclinical studies, an important step toward clinical trials, and to determine whether this brain energy pathway also plays a role in other metabolic brain diseases.

Funding: This work was supported by a donation from Bruce and Anthea McBryde.

Published in journal: Nature Metabolism

Title: DDHD2 provides a flux of saturated fatty acids for neuronal energy and function

Authors: Authors: Saber H. Saber, Nyakuoy Yak, Xuan Ling Hilary Yong, Yih Tyng Bong, Hannah Leeson, Chuan-Yang Dai, Tobias Binder, Siyuan Lu, Reshinthine Purushothaman, An-Sofie Lenaerts, Leonardo Almeida-Souza, Lidiia Koludarova, Safak Er, Irena Hlushchuk, Arnaud Gaudin, Sachin Singh, Tuula A. Nyman, Jeffrey R. Harmer, Steven Zuryn, Ernst Wolvetang, Gert Hoy Talbo, Mikko Airavaara, Brendan J. Battersby, Ashley J. van Waardenberg, Victor Anggono, Giuseppe Balistreri, and Merja Joensuu

Source/Credit: University of Queensland

Edited by: Scientific Frontline

Reference Number: bmol100125_01

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