The C9ORF72 repeat expansion alters neurodevelopment

Genetic mutations that cause adult-onset neurodegenerative diseases are often expressed during embryonic stages, but it is unclear whether they alter neurodevelopment and how this might influence disease onset. Here, we show that the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a repeat expansion in C9ORF72 , restricts neural stem cell proliferation and reduces cortical and thalamic size in utero. Surprisingly, a repeat expansion-derived dipeptide repeat protein (DPR) not known to reduce neuronal viability plays a key role in impairing neurodevelopment. Pharmacologically mimicking the effects of the repeat expansion on neurodevelopment increases susceptibility of C9ORF72 mice to motor defects. Thus, the C9ORF72 repeat expansion stunts development of the brain regions prominently affected in C9ORF72 FTD/ALS patients.

Automated summary

This study reveals that a genetic mutation, C9ORF72 repeat expansion, not only restricts neural stem cell proliferation and reduces cortical and thalamic size in utero, but also impairs neurodevelopment through the expression of a repeat expansion-derived dipeptide repeat protein (DPR). Pharmacological simulation of the effects of the repeat expansion on neurodevelopment increases susceptibility to motor defects in C9ORF72 mice. This research highlights the importance of understanding the impact of genetic mutations on neurodevelopment in the onset of neurodegenerative diseases.