{"id":10872,"date":"2025-02-28T09:14:58","date_gmt":"2025-02-28T08:14:58","guid":{"rendered":"https:\/\/www.uni.lu\/lcsb-en\/?post_type=news&p=10872"},"modified":"2025-03-21T13:01:35","modified_gmt":"2025-03-21T12:01:35","slug":"rare-disease-day-2025","status":"publish","type":"news","link":"https:\/\/www.uni.lu\/lcsb-en\/news\/rare-disease-day-2025\/","title":{"rendered":"Rare Disease Day 2025: The LCSB lights up to support 300 million people worldwide"},"content":{"rendered":"
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On Rare Disease Day<\/a> 2025, the Luxembourg Centre for Systems Biomedicine (LCSB)<\/a> of the University of Luxembourg illuminates once again its building in blue, green, pink, and purple, joining buildings across Luxembourg and around the world. This show of solidarity, organised in partnership with ALAN, the Luxembourg association for rare diseases<\/a>, pays tribute to the 300 million people diagnosed worldwide with one of the more than 6000 known rare diseases, including 30,000 in Luxembourg. Many of these diseases start in childhood, are severe and still incurable, having profound impacts on patients, families, and caregivers. Rare Disease Day highlights the urgent need for continued support and increased investment in research to develop effective treatments or even cures. The LCSB is committed to uncovering the genetic and molecular mechanisms behind rare metabolic diseases. The Enzymology and Metabolism group<\/a>, led by Prof. Carole Linster<\/a>, is at the forefront of this effort.<\/p>\n\n\n\n

\nAdvancing research on rare neurometabolic diseases<\/strong><\/h2>\n\n\n\n

The group uses advanced biochemical and omics techniques to explore rare neurometabolic disorders and potential therapeutic strategies. For example, with international collaborators they discovered a rare childhood disease<\/a>, called PEBEL, resulting from mutations in the NAXD<\/em> or NAXE<\/em> genes. These mutations disrupt the body’s metabolite repair system, which normally acts like a cellular maintenance crew, clearing away toxic by-products. When this clean-up process fails, harmful substances build up, leading to progressive brain damage and other severe symptoms seen in PEBEL. <\/p>\n\n\n\n

Based on the team\u2019s work, clinicians found<\/a> that niacin (a form of vitamin B3) could help reduce some of the symptoms linked to these genetic mutations, highlighting the potential for nutritional and small molecule drug interventions to enhance rare disease outcomes. In a recent article, published in Cellular & Molecular Biology Letters<\/em><\/a>, Prof. Carole Linster and her team took this idea further. They used cell cultures to test a theory originally developed from a yeast model. Their experiments confirmed that toxic metabolites build up in cells lacking the NAXD<\/em> enzyme. These metabolites block the activity of another important enzyme, called 3-phosphoglycerate dehydrogenase, that plays a key role in the serine biosynthesis pathway. Without enough serine, many cellular processes are disrupted, which could help explain the symptoms seen in children with PEBEL. The researchers also discovered that this metabolic blockage becomes worse when cells are exposed to metabolic stress. <\/p>\n\n\n\n

In addition, the team found a potential way to help the cells recover: Supplementation with nicotinamide riboside (NR), another form of vitamin B3, and inosine partially restored serine production and improved cell function. <\/em>\u201cWhile we confirmed the known beneficial effect of vitamin B3 supplementation, we found that NR specifically and other supplements, such as inosine, could have an even better effect, either as replacements for vitamin B3 or in combination with it,\u201d explains Prof. Linster. \u201cBy gaining deeper insights into the molecular mechanisms of the disease in cell culture models, we not only enhance our understanding of the enzymatic processes involved but also pave the way for more effective, optimised treatment strategies.\u201d <\/em>These small molecules could indeed serve as promising therapeutic candidates for rare neurometabolic disorders such as PEBEL disease.<\/p>\n\n\n\n

Collaborations with researchers in Australia and internal partnerships within the LCSB, including the Developmental and Cellular Biology group<\/a> led by Prof. Jens Schwamborn and the Metabolomics and Lipidomics Platform<\/a>, were integral to the success of the study. Future preclinical research using animal models, such as zebrafish and mice, will further investigate the therapeutic potential of these compounds.<\/p>\n\n\n\n

\nLearning from rare diseases to tackle more widespread metabolic disorders<\/strong><\/h2>\n<\/div><\/section>\n\n\n
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Building on their expertise in enzyme function discovery and metabolite repair disorders, the researchers recently applied their know-how to a gene that is more commonly mutated in the human population and strongly linked with vitamin B12 deficiency, which in turn is associated with neurodegenerative diseases, particularly in individuals with low dietary intake of the vitamin.

In their latest study, recently published in Nature Chemical Biology<\/em><\/a>, Prof. Carole Linster and her team have discovered that this vitamin B12-linked gene encodes a new metabolite repair enzyme called CLYBL. Acting like a “clean-up crew,” CLYBL efficiently breaks down malyl-CoA to safeguard vitamin B12-dependent processes.<\/p>\n\n\n\n