| Summary: | <p>The GGGGCC hexanucleotide expansion in the C9orf72 gene (C9-HRE) is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9-ALS/FTD describes the condition in which patients suffer from both ALS and FTD, which are described as the degeneration of motor or cortical neurons, respectively. While the molecular phenotype caused by the C9-HRE is relatively well established in motor neurons, little work has been done to understand the molecular effect of the C9-HRE on cortical neurons.</p>
<p>This study aims at furthering our understanding of the molecular impairments caused by the C9-HRE in patient cortical neurons. To this end, I differentiated C9-ALS/FTD-patient induced pluripotent stem cells (iPSCs) into cortical neurons. In these cells, I measured stress granule formation, autophagic flux, ER stress, excitability, Ca2+ signalling, and mitochondrial integrity and function, which are pathways that are commonly affected in C9-HRE-carrying motor neurons. </p>
<p>I found no evidence of altered stress granule formation, autophagic flux, and ER stress in C9-iPSC-derived cortical neurons. Furthermore, I discovered changes in excitability, excitation latency, and cytosolic Ca2+ clearance after glutamate and KCl stimulation due to changes in GluA1 expression in cortical neurons. In addition, C9-iPSC-derived cortical neurons displayed mitochondrial impairments. The mitochondrial membrane potential was reduced causing increased mitophagy which results in a reduction in mitochondrial mass. The mitochondrial fission apparatus was downregulated, and the anterograde axonal transport machinery was overexpressed. Mitochondrial respiration remained unaltered in patient cortical neurons.
Together this data suggests the C9-HRE causes a distinct phenotype in iPSC-derived cortical neurons, stressing the need to study the FTD pathomechanism in the respective cell type. The molecular early-disease phenotype of C9-FTD includes impairments in excitability and mitochondrial processes. This study serves as a foundation for future FTD research using iPSC-derived cortical neurons.</p>
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