Neurodegenerative diseases are usually diagnosed in middle-aged or older adults, but those affected may have structural differences in the brain that appear before birth, as a new study has found that the most common genetic cause of amyotrophic lateral sclerosis ( ALS) and frontotemporal dementia (FTD) damage neural stem cells and decrease the size of two key areas of the brain during embryonic development.
The research was conducted by scientists at the USC Keck School of Medicine, who used patient-derived nerve cells and laboratory mice to demonstrate this. “We are just beginning to understand how neurodevelopment in an embryo can contribute to neurodegeneration in an adult,” said Justin Ichida, John Douglas French Alzheimer Foundation associate professor of stem cell biology and regenerative medicine at the Keck School of Medicine. from USC, and author of the paper. “Our study offers some suggestive evidence for how this might occur in the context of ALS and FTD.”
Up to 10% of ALS and FTD cases are due to mutations in the C9ORF72 gene, although these diseases usually manifest in very different ways. While ALS causes progressive paralysis that leads to death within three to five years of diagnosis, FTD generally affects behavior, personality, and language.
“C9ORF72 mutations impair neurodevelopment in patients with ALS and FTD and this could contribute to the onset of disease symptoms later in life”
In both cases, they manifest in middle age, or later, which is when patients are diagnosed; however, carriers of the C9ORF72 mutation can present reductions in the size of two areas of the brain (the thalamic region and the cortical region). frontal) decades before developing any symptoms. “It is unclear whether this reduction in gray matter is due to developmental disturbance in an embryo or early degeneration in an adult,” said first author Eric Hendricks, a postdoc in the Ichida Laboratory.
Alterations in the neurological development of the embryo
Hendricks and his colleagues decided to investigate this and obtained skin or blood cells from patients with ALS or frontotemporal dementia caused by mutations in C9ORF72 and reprogrammed these cells into neural stem cells, which are the cells that form the nervous system during embryonic development. They then found that, compared to neural stem cells from healthy people, neural stem cells from patients with ALS or FTD were unable to renew their population. In contrast, patient-derived neural stem cells had a tendency to differentiate prematurely into mature neurons.
The patient-derived neural stem cells contained a mutant protein called poly(AP). Although poly(AP) is not fatally toxic to cells, it does impair their ability to make proteins needed to make new cells. As a result, poly(AP) alters the ability of neural stem cells to renew their population.
The scientists wanted to understand the consequences of an unrenewed population of neural stem cells in a living organism and used laboratory mice. In embryonic mice, mutations in C9ORF72 caused developmental changes that could be measured both in their brains and in other parts of their bodies. In their brains, these changes included smaller thalamic regions, as well as reduced cortical thickness. Mice also weighed 5-10% less at embryonic day 18.5.
They also found that if they administered a drug that caused similar structural changes in the brain during embryonic development, the mice experienced clumsiness and other motor deficits at two months of age. “Our findings suggest that C9ORF72 mutations impair neurodevelopment in patients with ALS and FTD, and that this could potentially contribute to the onset of disease symptoms later in life,” concludes Ichida. Her findings have been published in Cell Reports.
