Cellular and Molecular Mechanisms of FUS-related ALS/FTD

FUS相关ALS/FTD的细胞和分子机制

基本信息

批准号：
10582582
负责人：
Udai B Pandey
金额：
$ 38.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582582
关键词：
ALS patients Amyotrophic Lateral Sclerosis Animal Model Animals Award Axon Behavioral Assay Biochemical Biogenesis Biological Assay Brain CAG repeat Cell Culture Techniques Cell model Cell physiology Complex Cytoplasm Cytoplasmic Granules Defect Disease Drosophila genus Ectopic Expression Frontotemporal Dementia Functional disorder Genes Genetic Genetic Screening Genetic Transcription Goals Homologous Gene Human Light Link Longevity Lower Organism Mammalian Cell Mediating MicroRNAs Modeling Molecular Motor Neurons Mutate Mutation Myotonic Dystrophy Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neurons Nuclear Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phosphorylation Physiological Proteins RNA RNA Interference RNA Splicing RNA metabolism RNA-Binding Protein FUS RNA-Binding Proteins SMN expression SMN protein (spinal muscular atrophy)Small Nuclear RNA Spinal Muscular Atrophy Therapeutic Intervention Toxic effect Translations Ubiquitin Vertebrates Work cellular pathology cofactor disease-causing mutation fly frontotemporal degeneration frontotemporal lobar dementia amyotrophic lateral sclerosis glycogen synthase kinase 3 beta human disease in vivo induced pluripotent stem cell knock-down molecular pathology motor neuron degeneration mutant novel patient subsets protein TDP-43 recruit stress granule trafficking transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

ALS 是一种迟发性进行性神经退行性疾病，由运动神经退行性疾病引起神经元中泛素阳性聚集物的积累是一种疾病的标志神经元细胞质。 FUS 被确定为家族性和散发性形式的基因突变肌萎缩侧索硬化症。事实上，一部分额颞叶痴呆 (FTD) 患者表现出 FUS 病理。 FUS 与 TDP-43 类似，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 中的发病机制尚不清楚。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）和果蝇概括人类疾病关键特征的模型，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 是出乎意料且新颖的突变体 FUS 毒性的修饰剂。 MBNL 蛋白，从低等生物到高度保守脊椎动物，与许多神经退行性疾病有关，例如强直性肌强直营养不良和 CAG 重复疾病。长期目标是确定 FUS 毒性的调节剂并利用哺乳动物细胞培养和果蝇了解其分子机制模型。我们当前应用程序的目标是确定muscleblind 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 muscleblind 和 drosha 调节 RNA 剪接、SG 动力学和 miRNA 生物合成受到 FUS 致病性突变的干扰。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进行了研究。我们期望剖析可用于开发治疗药物的分子途径针对 ALS/FTD 患者的干预措施。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.

DOI：
10.1093/hmg/ddw232
发表时间：
2016-09-15
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Crippa V;Cicardi ME;Ramesh N;Seguin SJ;Ganassi M;Bigi I;Diacci C;Zelotti E;Baratashvili M;Gregory JM;Dobson CM;Cereda C;Pandey UB;Poletti A;Carra S
通讯作者：
Carra S

Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy.

DOI：
10.1016/j.neuron.2014.12.031
发表时间：
2015-01-07
期刊：
NEURON
影响因子：
16.2
作者：
Scaramuzzino, Chiara;Casci, Ian;Parodi, Sara;Lievens, Patricia M. J.;Polanco, Maria J.;Milioto, Carmelo;Chivet, Mathilde;Monaghan, John;Mishra, Ashutosh;Badders, Nisha;Aggarwal, Tanya;Grunseich, Christopher;Sambataro, Fabio;Basso, Manuela;Fackelmayer, Frank O.;Taylor, J. Paul;Pandey, Udai Bhan;Pennuto, Maria
通讯作者：
Pennuto, Maria

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity.

DOI：
10.1007/s00401-015-1530-0
发表时间：
2016-04
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
Daigle JG;Krishnamurthy K;Ramesh N;Casci I;Monaghan J;McAvoy K;Godfrey EW;Daniel DC;Johnson EM;Monahan Z;Shewmaker F;Pasinelli P;Pandey UB
通讯作者：
Pandey UB

Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo

DOI：
10.1016/j.stemcr.2019.01.015
发表时间：
2019-03-05
期刊：
STEM CELL REPORTS
影响因子：
5.9
作者：
Reinhardt, Lydia;Kordes, Susanne;Sterneckert, Jared L.
通讯作者：
Sterneckert, Jared L.

Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.

DOI：
10.1016/j.neuron.2014.12.010
发表时间：
2014-12-17
期刊：
Neuron
影响因子：
16.2
作者：
Wen X;Tan W;Westergard T;Krishnamurthy K;Markandaiah SS;Shi Y;Lin S;Shneider NA;Monaghan J;Pandey UB;Pasinelli P;Ichida JK;Trotti D
通讯作者：
Trotti D