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Molecular mechanism underlying pathology in C9FTD/ALS | Pros | Cons |
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Loss-of-function | C9orf72 loss-of-function models in C. elegans and zebrafish result in motor neuron degeneration | C9orf72 loss-of-function mouse models do not show phenotype characteristic for ALS and FTD |
Carriers of C9orf72 HRE have decreased levels of C9orf72 mRNA and proteins in the brain | Patients homozygous for C9orf72 repeat expansion do not have more severe symptoms of disease |
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RNA-mediated gain-of-function | HRE-containing RNA transcripts accumulate and form nuclear aggregates, or RNA foci, in the brain of patients with mutated C9orf72 | Drosophila models of RNA toxic gain-of-function fail to produce neurodegeneration |
Sequestration of RNA-binding proteins into RNA foci can disrupt RNA processing, translation, nucleocytoplasmic transport, and granule transport and lead to nucleolar stress | The results on RNA toxic gain-of-function mouse models are conflicting and need to be further investigated |
Higher abundance of RNA foci in patients carrying C9FTD/ALS HRE is associated with earlier disease onset |
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Protein-mediated gain-of-function | Drosophila model of protein-mediated gain-of-function develops neurodegeneration | Amounts of DPR in the brain do not correlate with clinical phenotype, severity of diseases, and neurodegeneration |
DPR disrupt nucleocytoplasmic transport, RNA processing, translation, ubiquitin proteasome system, formation of stress granule, and Notch signalling pathway and can lead to nucleolar stress | Abundance of DPR is low in the brain regions most affected by ALS and FTD |
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