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SMN dysfunction in FUS-dependent ALS

FUS 依赖性 ALS 中的 SMN 功能障碍

基本信息

批准号：
9227825
负责人：
Livio Pellizzoni
金额：
$ 24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9227825
关键词：
Address Adolescent Adult Age Alleles Amyotrophic Lateral Sclerosis Anabolism Animal Model Biogenesis Biological Assay Biological Models Biology Birth Cell model Cessation of life Child Code Complex Defect Denervation Disease Disease Pathway ES Cell Line Etiology Evaluation Event Familial Amyotrophic Lateral Sclerosis Fibroblasts Foundations Functional disorder Gene Delivery Genes Genetic Genotype Histones Human In Vitro Induced Mutation Infant Mortality Injection of therapeutic agent Knowledge Lasers Link Mammalian Cell Mediating Mendelian disorder Messenger RNA Microdissection Minority Modeling Molecular Molecular Genetics Monitor Motor Motor Neuron Disease Motor Neurons Mus Mutant Strains Mice Mutation Nature Nerve Degeneration Nervous system structure Nuclear Pathogenesis Pathology Pathway interactions Patients Phenotype Process Property Protein Isoforms RNA RNA Processing RNA Splicing RNA-Binding Proteins Risk Role SMN protein (spinal muscular atrophy)SMN1 gene Series Severity of illness Small Nuclear Ribonucleoproteins Solid Spinal Spinal Cord Spinal Muscular Atrophy Staging Testing Toxic effect Transgenic Mice Transgenic Organisms Untranslated RNA Work behavior test clinical phenotype defined contribution design gain of function gene product human disease mRNA Precursor motor disorder motor neuron degeneration motor neuron function mouse model mutant nervous system disorder neuromuscular novel overexpression research study sarcoma skeletal muscle wasting snRNP Biogenesis survival motor neuron gene therapeutic target

项目摘要

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are fatal neurological disorders that involve the selective degeneration of spinal motor neurons. SMA – the most common genetic cause of infant mortality – is a monogenic disorder caused by widespread deficiency in the survival motor neuron (SMN) protein due to deletion of the SMN1 gene. In contrast, ALS is predominantly a sporadic disorder, but in a minority of familial cases, mutations in over 20 different genes cause motor neuron degeneration. Genetic and molecular studies increasingly suggest that ALS and SMA may share common underlying mechanisms of disease. This project focuses on one form of familial ALS caused by mutations in the RNA binding protein fused in sarcoma (FUS) - which are associated with a broad range of clinical phenotypes including some of the most aggressive, juvenile-onset forms of the disease - and the possible role of SMN biology in the pathogenesis of FUS-dependent motor neuron degeneration. SMN has a well-established function in the assembly of small nuclear ribonucleoproteins (snRNPs) involved in diverse mRNA processing pathways and increasing evidence links SMN-dependent RNA dysregulation with the etiology of SMA. Remarkably, recent studies in cultured mammalian cells and ALS patients' fibroblasts have shown that FUS depletion or expression of ALS-linked FUS mutations disrupt the normal localization of SMN to nuclear bodies known as Gems. Furthermore, FUS has been shown to associate with SMN as well as specific snRNPs whose biogenesis is SMN-dependent and might be disrupted by ALS-linked FUS mutations. Together, these findings suggest that FUS and SMN are functionally linked through a shared molecular pathway(s) and support the view that SMA and ALS are related motor neuron diseases. However, the normal requirement of FUS for snRNP biogenesis and the pathogenic impact of FUS mutations on SMN biology have not yet been defined mechanistically, and the contribution of SMN dysfunction to FUS-ALS pathology remains unknown. To address these outstanding questions directly, our project takes a systematic, multi-disciplinary approach involving novel mouse models of FUS-dependent ALS to explore potential SMN-dependent mechanisms of FUS-mediated motor neuron degeneration. In Aim 1, we will investigate the phenotypic effects of both reduced and increased SMN expression on FUS-dependent motor neuron pathology in mouse models of ALS. In Aim2, we will employ a comprehensive set of molecular approaches to establish the functional relevance of normal and pathogenic FUS-SMN interactions in the pathway(s) of snRNP biogenesis in motor neurons using a combination of cellular and animal model systems. Collectively, these studies aim to establish convergent mechanisms in ALS and SMA and will yield a more complete understanding of the biology of FUS and SMN that is relevant to motor neuron survival. Identification of shared molecular pathways contributing to death and dysfunction of motor neurons in SMA and ALS may also expand the range of therapeutic targets for these diseases.

肌萎缩侧索硬化症 (ALS) 和脊髓性肌萎缩症 (SMA) 是致命的神经系统疾病，涉及脊髓运动神经元的选择性变性。 SMA——婴儿最常见的遗传原因死亡率——是一种单基因疾病，由存活运动神经元 (SMN) 普遍缺乏引起由于SMN1基因缺失而产生的蛋白质。相比之下，ALS 主要是一种散发性疾病，但在在少数家族性病例中，超过 20 个不同基因的突变会导致运动神经元变性。遗传和分子研究越来越多地表明 ALS 和 SMA 可能具有共同的潜在机制疾病。该项目重点研究由 RNA 结合蛋白突变引起的一种家族性 ALS 融合肉瘤 (FUS) - 与广泛的临床表型相关，包括一些该疾病最具侵袭性、青少年发病的形式——以及 SMN 生物学在该疾病中的可能作用 FUS 依赖性运动神经元变性的发病机制。 SMN在该领域具有完善的功能参与不同 mRNA 加工途径的小核核糖核蛋白 (snRNP) 的组装越来越多的证据将 SMN 依赖性 RNA 失调与 SMA 的病因联系起来。值得注意的是，最近对培养的哺乳动物细胞和 ALS 患者的成纤维细胞的研究表明，FUS 耗尽或 ALS 相关 FUS 突变的表达破坏了 SMN 到核体的正常定位，称为宝石。此外，FUS 已被证明与 SMN 以及特定的 snRNP 相关，其生物发生依赖于 SMN，并且可能会被 ALS 相关的 FUS 突变所破坏。综合起来，这些发现表明 FUS 和 SMN 通过共享的分子途径在功能上相连，并支持认为SMA和ALS是相关的运动神经元疾病。然而，FUS 的正常要求 snRNP 生物发生和 FUS 突变对 SMN 生物学的致病影响尚未明确从机制上讲，SMN 功能障碍对 FUS-ALS 病理学的影响仍不清楚。致地址直接这些悬而未决的问题，我们的项目采取了系统的、多学科的方法，涉及新颖的 FUS 依赖性 ALS 小鼠模型，探索 FUS 介导的潜在 SMN 依赖性机制运动神经元变性。在目标 1 中，我们将研究减少和增加的表型效应 ALS 小鼠模型中 FUS 依赖性运动神经元病理学中 SMN 的表达。在 Aim2 中，我们将采用一套全面的分子方法来确定正常和致病的功能相关性 FUS-SMN 在运动神经元 snRNP 生物发生途径中的相互作用和动物模型系统。总的来说，这些研究旨在建立 ALS 和 SMA 将使您对与运动相关的 FUS 和 SMN 生物学有更全面的了解神经元存活。鉴定导致死亡和运动功能障碍的共享分子途径 SMA 和 ALS 中的神经元也可能扩大这些疾病的治疗靶点范围。