New Worm Model May Help in More Quickly Finding Ways to Treat X-ALD, Study Shows

New Worm Model May Help in More Quickly Finding Ways to Treat X-ALD, Study Shows
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A new genetically modified earthworm model, Caenorhabditis elegans (C. elegans), mimics the features of human X-linked adrenoleukodystrophy (X-ALD), and could help in more quickly finding targets for therapies and at lower cost, a study reported.

Both are important considerations in X-ALD, which currently has no targeted treatments.

The study, “The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy,” was published in the journal Free Radical Biology and Medicine.

X-ALD is a neurodegenerative disease caused by mutations in the ABCD1 gene, which lead to the accumulation of a type of fat, called saturated very long-chain fatty acids (VLCFA), in tissues that include the brain and spinal cord.

The ABCD1 gene codes for the adrenoleukodystrophy protein (ALDP) that is responsible for the transport of VLCFA to peroxisomes, where they are degraded. The buildup of VLCFA damages myelin, the fatty layer that surrounds and protects nerve fibers. As a result, patients often experience neurological and mobility impairments, often accompanied by hormonal problems.

A team led by researchers at the Institut d’Investigacio Biomedica de Bellvitge (IDIBELL) in Spain developed a genetically modified earthworm, a widely used model in research called C. elegans, that is deficient for the protein analog to the human ALDP, called pmp-4.

C. elegans is a small transparent worm that measures about 1 millimeter, yet it has a very complex structure and shares the same metabolic pathways as people. Around 40 percent of its genes are similar (homologous) to human genes. Additionally, all neuronal populations found in the human brain can also be found in this worm.

Unlike mice, this animal model is easy to obtain at a low cost and in large numbers, thanks to its high reproductive rate.

When researchers removed the Pmp-4 gene from C. elegans, they observed that VLCFAs accumulated in the worms.

Like in X-ALD patients, these worms also showed similar changes in lipid (fat) metabolism, an oxidative imbalance in mitochondria (the cells’ energy source), and neurological conditions. Likewise, these worms were seen to have damage in their axons (nerve fibers), and difficulties with mobility.

“This model of adrenoleukodystrophy in C. elegans is a very valuable genetic tool that will allow us to study the mechanisms involved in the disease, and to find pharmacological targets faster than with other animal models, such as mice, which are much more complex and involve a costly and economically expensive process,” Esther Dalfó, a co-lead study author, said in a press release.

When researchers used a mitochondrial-targeted antioxidant called MitoQ, the size of lipid (fat) droplets in worm cells returned to normal. This was accompanied by a lessening of both axonal degeneration, and improved locomotion.

Taken together, these results suggested that targeting mitochondrial metabolism may have therapeutic benefits for X-ALD.

“This new animal model has helped us to confirm that oxidative stress caused by mitochondria (the energy-producing organelles of cells) is the major cause of neuronal damage in adrenoleukodystrophy, and this mechanism of damage is conserved from the worm to the patient,” said Aurora Pujol, a professor at IDIBELL and the study’s other co-lead author.

“The data point to new therapeutic pathways, such as mitochondrial antioxidants,” Pujol added.

Moreover, preliminary data from this X-ALD worm model suggest that glial cells — cells that offer support to neurons, and are involved in several key functions — are responsible for the neurological damage caused by the disease.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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