A rare mutation in children triggers the death of neurons through a recently discovered mechanism, according to a new study on neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Although dementia is usually associated with old age, there are also rare forms of pediatric dementia linked to more than 100 different genetic diseases. The analysis of such dramatic cases provides researchers with essential information about how neurodegeneration occurs, according to News.ro.
Recent experiments, carried out on an ultra-rare genetic mutation associated with severe neurodegeneration in children, have allowed the identification of a new mechanism that triggers the death of neurons.
The research suggests that the same cell death pathways could be involved in other brain diseases, such as Alzheimer’s, Parkinson’s or Huntington’s.
How the study was conducted
The study was coordinated by a team from the German research center Helmholtz Munich, which showed that mutations in a single gene cause, in mice, progressive inflammation and neuronal death.
In laboratory-grown human brain cells obtained from skin cells of patients with the same mutation, the neurons showed a very similar pattern of cell death.
The specific form of cell death identified is called ferroptosis, a type of programmed cell death triggered by iron accumulation and oxidative damage to the cell membrane.
Analysis of proteins expressed by neurons showed that this mechanism resembles processes previously described in dementia, and recent evidence has already linked ferroptosis to Alzheimer’s disease.
The genetic condition studied in humans is called Sedaghatian spondylometaphyseal dysplasia (SSMD), an extremely rare disease characterized by severe abnormalities of the brain and skeleton. It was described for the first time in 1980, and since then only a few dozen cases have been officially reported, many of them involving the death of children in the first months of life.
What the researchers discovered
Genomic sequencing showed that SSMD is linked to mutations in the gene encoding the GPX4 enzyme, considered a “protector” against ferroptosis, because it protects cell membranes from oxidative damage.
Although mutations in this gene do not necessarily lead to early-onset dementia, experiments on mouse cells and mini-brains obtained in the laboratory show how GPX4 protects neurons and how its dysfunction can lead to cell death.
The research focused on three children with SSMD in the United States who had varying degrees of brain atrophy and mutations in the same functional region of the GPX4 gene, and the data was then used for further studies in animal models and in nerve cells obtained from a patient’s skin cells.
The Director of the Institute of Metabolism and Cell Death at Helmholtz Munich, Marcus Conrad, explained that, normally, the GPX4 enzyme anchors in the cell membrane and quickly neutralizes lipid peroxides as they form. In the case of the studied mutation, this “anchor” is missing, and the enzyme can no longer fulfill the function of protecting the neuron.
Neurons grown in the laboratory from the stem cells of SSMD patients have been shown to be particularly vulnerable to ferroptosis, and blocking this process, with a chemical compound used experimentally in mice and in cell cultures, slowed neuronal death. The researchers emphasize that these substances are not approved for clinical use.
Dementia research has long focused on protein deposits in the brain, such as beta-amyloid plaques, but this study shifts the focus to cell membrane damage as the initial event of neuronal degeneration.
The authors of the study show that establishing the link between a structural feature of an enzyme and a severe human disease required almost 14 years of research, emphasizing the importance of long-term funding of basic research and international multidisciplinary collaboration.
The study was recently published in the journal Cell.
