The discovery that could change lives

In a rare brain disorder called Hereditary Spastic Paraplegia 54 (HSP54), the DDHD2 protein fails to function properly. When this happens, neurons lose their ability to generate fats needed for energy and normal operation, leading to early and progressively worsening communication problems between nerve cells.

Children affected by HSP54 often begin showing difficulties with movement and thinking at a young age. However, this new finding offers reason for optimism. In laboratory experiments, scientists treated damaged neurons with specific fatty acid supplements and found that within just 48 hours, the cells regained their energy production and normal activity.

"This is a real game-changer," said Dr. Merja Joensuu, who conceived the project and led the study at the Australian Institute for Bioengineering and Nanotechnology. "We've shown that healthy neurons rely on fats for fuel, and when this pathway fails in conditions like HSP54, it may be possible to repair the damage and reverse the neuropathologies."

New technologies fueling progress

The researchers are now preparing for the next phase of their work, which involves testing the safety and effectiveness of fatty acid-based treatments in pre-clinical models. These studies will determine whether similar approaches could eventually be used in humans, and whether this fat-based energy system might also play a role in treating other neurological diseases that currently lack effective therapies.

"We will continue the exciting collaboration with new non-invasive technologies to image the brain and therefore aid a faster development of the potential therapy. This breakthrough doesn't just rewrite the textbooks, it could transform lives" Dr. Giuseppe Balistreri from the University of Helsinki says.

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"This study is exciting because we found a new gene mutation that's linked to deafness, and more importantly we have a therapeutic target that can actually mitigate this condition," said lead author Rong Grace Zhai, PhD, Jack Miller Professor for the Study of Neurological Diseases of Neurology at UChicago. Although the study focused on individuals with a rare combination of mutations to the CPD gene, there could be broader implications if single mutations are linked to age-related hearing loss, she added.

The connection between CPD and hearing loss

Researchers began investigating CPD after identifying an unusual combination of mutations in three unrelated Turkish families affected by sensorineural hearing loss (SNHL), a congenital and hereditary condition that causes permanent deafness.

SNHL is typically diagnosed in early childhood and has long been considered irreversible. Hearing aids and cochlear implants can help improve perception of sound, but no direct medical treatment exists to repair the underlying damage.

When the scientists expanded their search through genetic databases, they discovered that individuals with other CPD mutations also showed signs of early-onset hearing loss, strengthening the link between this gene and auditory function.

How CPD protects sensory cells

To understand how CPD influences hearing, the team conducted experiments using mice. The CPD gene normally produces an enzyme responsible for generating the amino acid arginine, which then helps create nitric oxide, a key neurotransmitter involved in nerve signaling. In the inner ear, mutations in CPD disrupted this process, triggering oxidative stress and the death of delicate sensory hair cells that detect sound vibrations.

"It turns out that CPD maintains the level of arginine in the hair cells to allow a quick signaling cascade by generating nitric oxide," Zhai explained. "And that's why, although it's expressed ubiquitously in other cells throughout the nervous system, these hair cells in particular are more sensitive or vulnerable to the loss of CPD."

Fruit fly experiments reveal possible treatments

The researchers also used fruit flies as a model to explore how CPD mutations affect hearing. Flies with the defective gene exhibited behaviors consistent with inner ear dysfunction, such as impaired hearing and balance issues.

To test potential treatments, scientists tried two approaches. One was to provide arginine supplements to replace what was lost due to the gene defect. The other was to use sildenafil (Viagra), a drug known to stimulate one of the signaling pathways disrupted by reduced nitric oxide. Both treatments improved cell survival in patient-derived cells and reduced hearing-loss symptoms in the fruit flies.

"What makes this really impactful is that not only do we understand the underlying cellular and molecular mechanism for this kind of deafness, but we also found a promising therapeutic avenue for these patients. It is a good example of our efforts to repurpose FDA approved drugs for treating rare diseases," Zhai said.

The study also demonstrates the value of fruit fly models for studying neurological diseases, including age-related conditions, Zhai noted. "They give us the capability to not only understand disease pathology, but also to identify therapeutic approaches," she said.

Expanding the research to broader populations

The researchers plan to continue studying how nitric oxide signaling functions in the inner ear's sensory system. They also aim to investigate how common CPD mutations are in larger populations and whether they might contribute to other forms of hearing loss.

"How many people carry variants in this gene and is there a susceptibility to deafness or age-dependent hearing loss?" she said. "In other words, is this a risk factor for other types of sensory neuropathy?"

The study included collaborators from multiple institutions, including the University of Miami, Ege University, Ankara University, Yüzüncü Yıl University, Memorial Şişli Hospital, the University of Iowa, and the University of Northampton (UK).