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Amyotrophic Lateral Sclerosis (ALS) is a severe neurological disease in which motor neurons gradually die off. This leads to progressive muscle weakness and eventually respiratory failure. The disease mainly affects middle-aged individuals and is often fatal within a few years. A common genetic cause is a mutation in the C9ORF72 (C9) gene, which is also linked to frontotemporal dementia (FTD).
 

This thesis investigates how the C9 mutation affects brain development at an early stage. To do this, researchers used brain organoids—three-dimensional clusters of cells grown from patient and healthy stem cells that mimic the structure and function of the human brain. These models allow scientists to study early cellular changes that are otherwise difficult to observe.
Organoids with the C9 mutation showed abnormalities in growth patterns, cell distribution, and brain-like structure, including smaller ventricular zones and altered positioning of neural progenitor cells. Using single-cell RNA sequencing, the study found that certain neuron types, such as deep-layer neurons, were less abundant in C9 organoids. Electrophysiological tests revealed impaired synaptic communication, especially due to a reduction in presynaptic structures. These findings suggest that C9-related changes begin long before symptoms appear.
Additionally, organoids were created from stem cells of symptom-free carriers of the C9 mutation. Although these individuals show no clinical signs, their organoids already displayed differences, such as altered growth and reduced expression of synapse-related genes.
 

This research enhances our understanding of early disease mechanisms and highlights the potential of brain organoids in developing targeted diagnostics and therapies for ALS and FTD.