Investigating the molecular basis for selective vulnerability in FET-linked Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal dementia (FTD)

RNA代谢障碍已成为神经退行性疾病的共同特征，突变的RNA结合蛋白已被确定为几种神经退行性疾病或神经发育障碍的遗传原因(Nussbacher等人，2015)。这些RNA结合蛋白中融合在肉瘤(FUS)、尤文肉瘤(EWS)和TATA盒结合蛋白相关因子15(TAF15)中，这些蛋白是高度保守的多功能核质穿梭蛋白，形成了所谓的FET家族(Riggi等人，2007；Tan和Manley，2009)。该项目的主要目的是深入了解FET蛋白在健康人的整个衰老过程中以及在FET相关的额颞叶痴呆患者组织中在中枢神经系统中的细胞类型特异性表达。这些相互关联的目标可以概括如下。用显微镜对FET蛋白在幼年和老年小鼠脑和脊髓中表达的时空分析。用RT-qPCR法分析FET基因在幼年和老年小鼠脑和脊髓中的表达比较分析人类对照和ALS/FTD脆弱和耐药患者组织中FET蛋白的表达。

Dysfunctional RNA metabolism has emerged as a common characteristic in neurodegeneration with mutated RNA binding proteins having been identified as the genetic cause of several neurodegenerative or neurodevelopmental disorders (Nussbacher et al., 2015). Among these RNA binding proteins are Fused in Sarcoma (FUS), Ewing Sarcoma (EWS), and TATA-Box Binding Protein Associated Factor 15 (TAF15), which are highly conserved multifunctional nucleocytoplasmic shuttling proteins that form the so-called FET family (Riggi et al., 2007; Tan and Manley, 2009). The main aims of this project are to gain insight into the cell type specific expression of the FET proteins in the CNS throughout ageing in health and in the context of FET-linked Frontotemporal Dementia in patient tissue. These interlinked aims can be summarised as follows. Temporospatial analysis of FET protein expression throughout the brain and spinal cord of young and aged mice using microscopy. Temporospatial analysis of FET gene expression throughout the brain and spinal cord of young and aged mice using RT-qPCR Comparative analysis of FET protein expression in human control and ALS/FTD vulnerable and resistant patient tissue.