Early Brain Changes May Hold Key to ALS and FTD

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A recent study published in Cell Reports sheds light on the relationship between neurodevelopmental processes during embryonic stages and the later onset of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Researchers from the University of Southern California (USC) utilized patient-derived nerve cells and laboratory mice to uncover how a common genetic mutation linked to ALS and FTD affects neural stem cells and leads to structural changes in the brain before birth. 

While ALS and FTD typically manifest in middle age or later, individuals carrying mutations in the C9ORF72 gene, responsible for up to 10% of ALS and FTD cases, exhibit reductions in the size of two critical brain regions—the thalamic and frontal cortical regions—decades before displaying any symptoms. The exact origin of this gray matter reduction—whether it arises from embryonic development or early degeneration in adulthood—remained uncertain. 

Lead author Eric Hendricks, a postdoctoral researcher at the USC Stem Cell Biology and Regenerative Medicine department, and his colleagues aimed to explore this question by utilizing patient-derived cells. Skin or blood cells from individuals with ALS or FTD due to C9ORF72 mutations were reprogrammed into neural stem cells, which play a pivotal role in forming the nervous system during embryonic development. 

Comparing these patient-derived neural stem cells to those from healthy individuals, the researchers discovered significant differences. Neural stem cells from ALS or FTD patients were unable to renew their population effectively and showed a tendency to prematurely differentiate into mature neurons. These cells harbored a mutant protein called poly (AP), which, while not fatally toxic to cells, disrupted their ability to produce essential proteins required for building new cells, hampering the renewal of neural stem cell populations. 

To further understand the consequences of non-renewing neural stem cell populations within a living organism, the scientists turned to laboratory mice. Mutations in the C9ORF72 gene during embryonic stages led to measurable developmental changes, not only in the brain but also throughout the body of the mice. In their brains, these changes included smaller thalamic regions and reduced cortical thickness.

Additionally, the embryonic mice exhibited a 5-10% lower body weight at embryonic day 18.5. Researchers also administered a drug that induced similar structural changes in the brains of embryonic mice. As a result, these mice displayed clumsiness and other motor deficits by the age of two months. 

The study’s corresponding author, Justin Ichida, who serves as the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, as well as a New York Stem Cell Foundation-Robertson Investigator, emphasized the implications of these findings. “Our findings suggest that C9ORF72 mutations impair neurodevelopment in utero in patients with ALS and FTD and that this could potentially contribute to the onset of disease symptoms later in life.” 

This research underscores the intricate relationship between early developmental processes and the later emergence of neurodegenerative diseases. While the exact mechanisms are still being unraveled, these insights may pave the way for the development of new strategies for early detection and intervention in ALS and FTD, potentially offering hope for improved patient outcomes in the future. 

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