Researchers have discovered how to safeguard the genome from the metabolic toxin formaldehyde in AMeD, a rare congenital condition linked to premature aging and myeloid leukemia. Utilizing human cells and a new animal model, the team was able to mimic AMeD symptoms, paving the way for potential new treatments.
A collaborative study led by scientists from the Josep Carreras Leukaemia Research Institute and the University of Cologne has revealed how the genome is protected against the metabolic toxin formaldehyde in AMeD, a rare genetic disorder associated with premature aging and myeloid leukemia. By employing human cells and a novel animal model to simulate symptoms of AMeD, their findings suggest new avenues for therapeutic strategies.
AMeD syndrome is a serious genetic disorder affecting children, characterized by accelerated aging, developmental delays, and bone marrow failure, which can progress to Myelodysplastic Syndrome and Acute Myeloid Leukemia. This condition arises from mutations in the ADH5 and ALDH2 genes, which play crucial roles in converting formaldehyde, an environmental toxin, into less harmful substances. In patients with AMeD, however, formaldehyde accumulates within cells, damaging cellular components and overwhelming the repair systems.
Formaldehyde is a simple yet highly reactive organic compound found in various sources, including building materials, household products, cigarette smoke, and automobile emissions. Additionally, it can be generated inside our own cells as a by-product of metabolism. During normal growth, cells naturally produce this reactive toxin, which, if not efficiently detoxified, can lead to problems. Fortunately, cells are equipped with numerous repair mechanisms that mitigate the damage caused by formaldehyde.
Researchers have long been curious about which detoxification and repair systems are most effective against formaldehyde toxicity, particularly since the compound can affect numerous cellular components, resulting in diverse types of damage that necessitate different repair methods. However, identifying an appropriate in vivo model has proven challenging until now.
A recent study led by Prof. Bjoern Schumacher from the University of Cologne, Germany, and Dr. Lucas Pontel from the Josep Carreras Leukaemia Research Institute, introduced a genetically manageable animal model of AMeD. This research, published in the journal Nucleic Acid Research, utilized the roundworm C. elegans and human cells derived from patients to determine the critical mechanisms that protect the genome from formaldehyde during various stages of development, adulthood, and aging.
The researchers uncovered at least three distinctive mechanisms that counteract DNA damage caused by formaldehyde: 1) In the germline and early embryonic stages, the primary repair method is Global Genome Nucleotide Excision Repair, a system adept at repairing DNA en masse, commonly employed to shield cells from UV damage. 2) In adult and non-dividing cells, where DNA replication is inactive, the canonical Transcription-Coupled Repair mechanism addresses formaldehyde toxicity by resolving DNA damage in actively transcribed genes. 3) During cell division in development, a specific branch of the Transcription-Coupled Repair system operates independently from the typical Nucleotide Excision Repair, effectively resolving DNA-protein crosslinks.
Identifying these crucial repair mechanisms for addressing formaldehyde-induced damage is significant. Furthermore, the research team found that the known antioxidant and formaldehyde neutralizer N-acetyl-L-cysteine (NAC) can reverse much of the toxicity observed in the AMeD animal model and in human cells with DNA repair deficiencies, providing an unexpected hint at a possible therapeutic approach to alleviate the harmful effects of formaldehyde.
Although this research remains in the preclinical stage, the scientists are optimistic that it may inspire new therapeutic and dietary strategies aimed at reducing the toxicity of this metabolic toxin, not solely for individuals with AMeD but also for those with a family history of cancer.
This research was partially supported by funding from the NIH (USA), the Deutsche José Carreras Leukämie-Stiftung, the Deutsche Forschungsgemeinschaft, the European Union Next Generation, and the Spanish Ministry of Science and Innovation. No AI systems were employed in creating this text.
