Jefferson researchers uncover abnormal gene programs tied to the disease’s earliest stages

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no cure and limited treatment options. One of the earliest signs of ALS is overactive brain signals known as cortical hyperexcitability. This activity appears even before motor neurons begin to degenerate and physical symptoms such as trouble walking or swallowing show up. Now, Thomas Jefferson University researchers have discovered that neurons carrying the most common genetic cause of ALS respond abnormally to cortical hyperexcitability. The findings offer fresh insight into how the disease takes hold.

The team focused on the most common genetic cause of ALS, a nucleotide repeat expansion in a gene called C9orf72, colloquially dubbed C9. To figure out how C9 affects brain cells known as cortical neurons, the researchers first turned stem cells from ALS patients into cortical neurons in a dish. Then, they asked how these cells react when stimulated in a way to mimic cortical hyperexcitability.

“The question was, do cells with the C9 mutation respond differently to the same stimulation? And the answer is yes, they do,” says Layla Ghaffari-Starr, lead researcher of the project and now Director of Disease Modeling at Synapticure, a health care provider for neurodegenerative diseases like ALS.

The scientists, members of Sidney Kimmel Medical College, found that even at baseline, C9 neurons were genetically different. When the researchers stimulated the cells, the C9 neurons activated divergent genetic programs compared with healthy ones. Some typical pathways were maintained, but others failed to turn on. In addition, aberrant programs were triggered, including some previously linked to ALS.

The findings may help explain the trajectory of the disease from early hyperexcitable states to later neuron loss, and could point to biomarkers for detecting ALS sooner.

“Our research serves as a resource to the ALS and scientific communities to look at dysregulated genes in C9 mutant neurons,” says Dr. Ghaffari-Starr. She and neuroscientist Aaron Haeusler, PhD,  have created an interactive dataset for researchers and the ALS community to identify therapeutic targets.

“It really takes everyone to solve this,” says Dr. Haeusler, who is especially grateful to the patients who donated their cells for research. “Without them, we wouldn’t be able to make these advancements.”

Source: Thomas Jefferson University