Researchers at the University of Southern California have shown that individuals carrying a mutation linked to frontotemporal dementia may exhibit structural brain differences that begin during prenatal development, well before symptoms of the condition emerge in middle age or later. The findings appear in Cell Reports.
About 10% of frontotemporal dementia cases and a portion of amyotrophic lateral sclerosis (ALS) cases are associated with mutations in the C9ORF72 gene. While these diseases share some genetic roots, their clinical pictures diverge: ALS gradually impairs movement and breathing, whereas frontotemporal dementia alters behavior, personality, and language.
Typically diagnosed in midlife or later, carriers of the C9ORF72 mutation show reductions in the size of two brain regions—the thalamus and the frontal cortex—long before any signs of illness appear. In a landmark study, researchers demonstrated that these prenatal brain differences can be detected during embryonic development.
The scientists conducted laboratory experiments using skin and blood samples from patients who carry the C9ORF72 mutation and have either frontotemporal dementia or ALS. These cells were reprogrammed into neural stem cells, the progenitors responsible for forming the nervous system during early development. When compared with cells from healthy individuals, neural stem cells derived from mutation carriers showed impaired growth and a tendency to differentiate into mature neurons sooner than expected.
The team traced this abnormal behavior to a mutant protein produced by the C9ORF72 mutation, known as polyAP, which appears to disrupt the normal pace of neural development. This disruption helps explain how early cellular changes might set the stage for later neurodegenerative symptoms, even if they do not become evident until adulthood.
In studies conducted with animal models, scientists observed that C9ORF72 mutations lead to measurable developmental changes beyond just the brain. The thalamic regions in mice showed shrinkage, and the thickness of the cerebral cortex decreased as development progressed. Moreover, the body weight of embryos at a particular stage was reduced by roughly 5 to 10 percent compared with typical development. These findings underscore a broader impact of the mutation on embryogenesis, not limited to neural tissue alone.
“We are just beginning to unravel how events in embryonic nervous system development might influence the progression of neurodegenerative disease later in life,” the researchers noted. They suggest that impaired neurodevelopment driven by C9ORF72 mutations may contribute to the onset and trajectory of ALS and frontotemporal dementia, offering a potential link between prenatal biology and adult disease.
The work emphasizes the importance of studying developmental processes to better understand why these conditions manifest when they do and how early cellular missteps can have long-term consequences for brain function. It also opens avenues for considering therapeutic strategies that target neurodevelopmental pathways with the aim of delaying or altering disease progression.
As science continues to map the cascade from embryonic development to adult neurodegeneration, researchers hope to clarify how prenatal brain growth patterns relate to symptom emergence in families affected by C9ORF72-related disorders and to identify opportunities for early intervention or prevention in future generations.
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