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

痴呆症和神经退行性变中神经元是如何死亡的？尽管早期有人提出，经典的细胞凋亡已被排除为大多数神经退行性疾病的神经细胞死亡机制，包括C9ORF72重复扩增突变引起的ALS/FTD(C9ALS/FTD)。我们最近发现了一种新的细胞死亡机制，称为核下垂，它在一些多谷氨酰胺疾病中起作用，涉及与自噬机制相关的Lamin B1的细胞质重新定位导致核形状退化。作为最终事件，Lamin B1以微囊的形式从细胞中分泌出来。扩展的C9ORF72转录本通过一种称为RAN翻译的机制产生二肽(DPR)，该机制具有毒性，并在细胞核中定位。在C9ALS/FTD病理模型中，已经描述了核形状的改变，C9ORF72蛋白与自噬有关。在这个博士项目中，学生将研究C9ORF72相关的二肽是否通过核完整性的退化导致ALS/FTD模型中的神经细胞死亡。

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.