Neuronal cell death by degeneration of nuclear integrity in C9orf72-associated ALS

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How do neurons die in dementia and neurodegeneration? Despite early suggestion, classic apoptosis has been ruled out as the mechanism of neuronal cell death in most neurodegenerative diseases, including ALS/FTD caused by repeat expansion mutation in C9ORF72 (C9ALS/FTD). We have recently discovered a novel cell death mechanism, named karyoptosis, which operates in some polyglutamine diseases involving the degeneration of nuclear shape by cytoplasmic relocalisation of Lamin B1 associated to the autophagy machinery. As the terminal event Lamin B1 is excreted from the cell in microvesicles.Expanded C9ORF72 transcripts give rise to dipeptides (DPR) through a mechanism called RAN translation, which exert toxicity and some localise in the nucleus. In models for C9ALS/FTD pathology, an alteration of the nuclear shape has been described, and C9Orf72 protein has been implicated in autophagy.In this PhD project, the student will address whether C9ORF72 -associated dipeptides cause neuronal cell death in models for ALS/FTD via the degeneration of nuclear integrity.