Cellular and Molecular Mechanisms of FUS-related ALS/FTD

肌萎缩侧索硬化症是一种迟发性进行性神经退行性疾病，由运动退行性改变引起。 神经元，疾病的标志是泛素阳性聚集在 神经元胞质。FUS被鉴定为在家族性和散发形式的FUS中的基因突变 肌萎缩侧索硬化。事实上，部分额颞性痴呆(FTD)患者表现出FUS病理。 FUS类似于TDP-43，是一种RNA结合蛋白，与RNA的多个方面有关 新陈代谢，包括剪接、运输和翻译。突变的精确机制 FUS在ALS发病机制中的作用尚不清楚。 为了了解FUS介导的神经退行性变的分子机制，我们开发了 细胞(哺乳动物初级神经元和病人来源的IPSC运动神经元)和果蝇 这些模型概括了人类疾病的关键特征，包括细胞质定位错误， 神经肌肉接头缺陷，运动功能障碍，寿命缩短，不安的压力 颗粒动力学和毒性。我们发现肌盲和DROSHA是意想不到的和新颖的 突变型FUS毒性修饰剂。MBNL蛋白，在低等生物中高度保守 脊椎动物与许多神经退行性疾病有关，如肌强直 营养不良和CAG重复疾病。长期目标是确定FUS毒性的修饰物。 并利用哺乳动物细胞培养和果蝇了解它们的分子机制 模特们。我们目前应用的目标是确定肌肉盲和DROSHA如何 调节果蝇和FUS iPSC运动神经元中FUS介导的毒性。我们假设 肌盲和DROSHA调控RNA剪接、SG动力学和miRNA生物发生，即 对FUS的致病突变感到不安。我们将研究肌肉盲人和 DROSHA关于FUS相关神经退行性变的细胞和分子病理学。我们预计 剖析可用于开发治疗药物的分子途径 对ALS/FTD患者的干预。

ALS is a late-onset progressive neurodegenerative disease caused by degeneration of motor neurons, and a disease hallmark is the accumulation of ubiquitin-positive aggregates in neuronal cytoplasm. FUS was identified as genes mutated in both familial and sporadic forms of ALS. In fact, a subset of patients with frontotemporal dementia (FTD) show FUS pathology. FUS, similar to TDP-43, is an RNA binding protein implicated in multiple aspects of RNA metabolism, including splicing, trafficking, and translation. The precise mechanisms of mutated FUS in ALS pathogenesis are not known. To understand the molecular mechanisms of FUS-mediated neurodegeneration, we developed cellular (mammalian primary neuronal and patient-derived iPSC motor neuron) and Drosophila models that recapitulate key features of human disease including cytoplasmic mislocalization, neuromuscular junction defects, locomotor dysfunctions, reduced life span, perturbed stress granule dynamics and toxicity. We discovered muscleblind and drosha as unexpected and novel modifiers of mutant FUS toxicity. MBNL proteins, highly conserved from lower organisms to vertebrates, have been implicated in many neurodegenerative disorders, such as myotonic dystrophy and CAG repeat diseases. The long-term goal is to identify modifiers of FUS toxicity and understand their molecular mechanisms using mammalian cell culture and Drosophila models. The objective of our current application is to determine how muscleblind and drosha modulate FUS-mediated toxicity in Drosophila and FUS iPSC motor neurons. We hypothesize that muscleblind and drosha regulate RNA splicing, SG dynamics and miRNA biogenesis that is perturbed by pathogenic mutations in FUS. We will examine the impact of muscleblind and drosha on cellular and molecular pathologies in FUS-associated neurodegeneration. We expect to dissect the molecular pathways that could be exploited for developing therapeutic interventions for ALS/FTD patients.