Pathophysiological role of the RNA-binding protein FUS in Dementia

神经退行性疾病，如阿尔茨海默病和额颞叶痴呆(FTD)，表现出共同的病理生理过程，经历突触功能障碍，最终在更大的神经元萎缩之前消除它们。因此，更好地了解突触功能，以及这种功能在发病早期是如何失调的，将为确定潜在的新治疗靶点带来进一步的见解。一种与FTD和ALS高度相关的关键蛋白在肉瘤(FUS)中融合。FUS是一种普遍表达的DNA/RNA结合蛋白，属于多功能DNA/RNA结合蛋白FET/Tet家族(Mackenzie，Rademaker&Neumann，2010)。FUS也已知在细胞核和细胞质之间穿梭(Zinszner等人，1997)。FUS还参与了树突的维持，树突是一种小的球状突起，接受大脑的大多数兴奋性突触连接，并支持认知功能(Kasai等人，2003)。总之，将FUS定位为突触功能的潜在调节因子。有趣的是，尽管ALS患者中存在FUS突变，通常位于脯氨酸-酪氨酸NLS(PY-NLS)，但到目前为止，在纯FTD/FTLD-FUS病例中还没有发现FUS突变，这引发了非突变FUS如何以及为什么会在这些患者中产生有害影响的问题(Nolan，Talbot&Ansorge，2016)。然而，FTLD患者的FUS冷凝物显示出FUS蛋白的低甲基化，这表明了一种潜在的机制(Neumann等人，2012年)。来自CHO小组的初步数据显示，在海马CA1神经元中过表达模拟低甲基化的FUS结构(FUS-16R；Qamar等人，2018)会在树突棘中产生FUS凝集，削弱AMPA和NMDA受体介导的兴奋性突触电流，并损害突触可塑性(未发表数据2022)。这些发现表明，FUS的低甲基化足以导致突触功能障碍，但FUS的低甲基化对其毒性作用的分子途径尚不清楚。因此，这项拟议的PHD项目将测试FUS低甲基化如何导致突触功能障碍，并可能提供痴呆症病理生理学的分子机制。

Neurodegenerative conditions such as Alzheimer's Disease and frontotemporal dementia (FTD) exhibit a common pathophysiology undergoing synapse dysfunction and ultimately their elimination prior to greater neuronal atrophy. Consequently, a greater understanding of synapse function, and how this is dysregulated in the early stage of pathogenesis will bring further insights to identify potential novel therapeutic targets. A key protein highly associated with FTD and ALS is fused in sarcoma (FUS). FUS is a ubiquitously expressed DNA/RNA-binding protein of the FET/TET family of multifunctional DNA/RNA binding proteins (Mackenzie, Rademakers & Neumann, 2010). FUS is also known to shuttle between the nucleus and the cytoplasm (Zinszner et al, 1997). FUS is also involved in the maintenance of dendritic spines, the small bulbous protrusions that receive most of the excitatory synaptic connections of the brain and underpin cognitive function (Kasai et al, 2003). Collectively, positioning FUS as a potential regulator of synapse function. Interestingly, even though FUS mutations are presents in ALS patients, usually located in the proline-tyrosine NLS (PY-NLS), no FUS mutations have been identified in pure FTD/FTLD-FUS cases to date, raising questions about how and why non-mutant FUS may be exerting detrimental effects in these patients (Nolan, Talbot & Ansorge, 2016). However, the FUS condensates in FTLD patients exhibited hypomethylation of the FUS proteins, indicating a potential mechanism (Neumann et al, 2012). Preliminary data from Cho group has revealed that overexpression of a FUS construct which mimics hypomethylation (FUS-16R; Qamar et al, 2018) in hippocampal CA1 neurons produces FUS condensates in dendritic spines, weakened AMPA- and NMDA-receptor mediated excitatory synaptic currents, and impaired synaptic plasticity (unpublished data 2022). These findings suggest FUS hypomethylation is sufficient to induce synaptic dysfunction, but the molecular pathways via with hypomethylated FUS exerts its toxic effects are unknown. Therefore, this proposed PhD project will test how FUS hypomethylation induces synapse dysfunction and may provide a molecular mechanism of pathophysiology in dementia.