Cellular and Molecular Mechanisms of FUS-related ALS/FTD

ALS是一种迟发性进行性神经退行性疾病， 神经元，疾病的标志是泛素阳性聚集体的积累， 神经细胞质FUS被鉴定为在家族性和散发性形式的FUS中突变的基因。 人症事实上，额颞叶痴呆（FTD）患者的一个子集显示FUS病理。 FUS与TDP-43相似，是一种RNA结合蛋白，涉及RNA的多个方面 代谢，包括剪接，运输和翻译。突变的确切机制 FUS在ALS发病机制中的作用尚不清楚。 为了了解FUS介导的神经变性的分子机制，我们开发了 细胞（哺乳动物原代神经元和患者来源的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，包括细胞质错误定位， 神经肌肉接头缺陷，运动功能障碍，寿命缩短，压力扰动 颗粒动力学和毒性。我们发现muscleblind和drosha是意想不到的和新奇的 突变FUS毒性的修饰剂。MBNL蛋白，从低等生物到 脊椎动物，已经涉及许多神经退行性疾病，如肌强直性疾病， 营养不良和CAG重复疾病。长期目标是确定FUS毒性的修饰剂 并利用哺乳动物细胞培养和果蝇来了解它们的分子机制 模型我们当前应用的目的是确定肌盲和drosha 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调节RNA剪接，SG动力学和miRNA生物合成， FUS中的致病性突变所干扰。我们将研究肌盲的影响， Drosha对FUS相关神经变性的细胞和分子病理学的研究。我们预计 来剖析分子途径， 对ALS/FTD患者进行干预。

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.