RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减

基本信息

批准号：
10206705
负责人：
Sami Barmada
金额：
$ 37.19万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2016-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206705
关键词：
ALS patients Adenosine Affect Amyotrophic Lateral Sclerosis Binding Binding Proteins C9ORF72 Cells Crystallization Cytoplasm Data Deposition Disease Equilibrium Failure Familial disease Family Frontotemporal Lobar Degenerations Funding Genes Genetic Genetic Transcription Goals Health Homeostasis Human Hypermethylation Impairment Individual Induced pluripotent stem cell derived neurons Interruption Introns Lead Maps Mediating Messenger RNA Methylation Microscopy Modeling Modification Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nitrogen Nuclear Protein Nuclear RNA Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Process Property Protein Splicing Proteins Proteome Quality Control RNA RNA Binding RNA Decay RNA Helicase RNA Instability RNA Splicing RNA Stability RNA chemical synthesis RNA-Binding Protein FUS RNA-Binding Proteins Reader RiboTag Ribosomal Proteins Sampling Spinal Cord Survival Analysis Testing Therapeutic Toxic effect Transcript Translations Work base cell type frontotemporal lobar dementia-amyotrophic lateral sclerosis knock-down mutant neuron loss neuronal survival neuroprotection novel overexpression particle prevent protein TDP-43 protein function response single molecule therapeutically effective

ALS patients Adenosine Affect Amyotrophic Lateral Sclerosis Binding Binding Proteins C9ORF72 Cells Crystallization Cytoplasm Data Deposition Disease Equilibrium Failure Familial disease Family Frontotemporal Lobar Degenerations Funding Genes Genetic Genetic Transcription Goals Health Homeostasis Human Hypermethylation Impairment Individual Induced pluripotent stem cell derived neurons Interruption Introns Lead Maps Mediating Messenger RNA Methylation Microscopy Modeling Modification Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nitrogen Nuclear Protein Nuclear RNA Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Process Property Protein Splicing Proteins Proteome Quality Control RNA RNA Binding RNA Decay RNA Helicase RNA Instability RNA Splicing RNA Stability RNA chemical synthesis RNA-Binding Protein FUS RNA-Binding Proteins Reader RiboTag Ribosomal Proteins Sampling Spinal Cord Survival Analysis Testing Therapeutic Toxic effect Transcript Translations Work base cell type frontotemporal lobar dementia-amyotrophic lateral sclerosis knock-down mutant neuron loss neuronal survival neuroprotection novel overexpression particle prevent protein TDP-43 protein function response single molecule therapeutically effective

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项目摘要

RNA decay is a critical component of RNA homeostasis. Transcriptionally active cells such as neurons have developed intricate pathways for regulating RNA turnover and balancing this process with RNA synthesis. During the initial funding period, we uncovered widespread abnormalities in RNA stability in cells from individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), implicating dysfunctional RNA clearance pathways in disease pathogenesis. We also showed that many of these abnormalities could be recapitulated by the deposition of TDP43, a nuclear RNA binding protein and splicing factor that is mislocalized to the cytoplasm in >95% of ALS patients and the most common subtype of FTLD (FTLD-TDP). In probing the downstream consequences of TDP43 deposition, we discovered that TDP43 accumulation preferentially affects the splicing of mRNAs encoding ribosomal proteins, leading to excessive intron retention and mRNA destabilization. Based on these results, we hypothesize that TDP43 mislocalization and accumulation in ALS and FTLD-TDP destabilizes ribosomal protein-encoding mRNAs, compromising translation and interfering with RNA decay mechanisms that rely on active translation, including nonsense-mediated RNA decay (NMD). Together, these phenomena would be expected to trigger a vicious cycle culminating in RNA and protein dyshomeostasis, and eventually neurodegeneration. The current proposal builds on data from the initial funding period to (i) elucidate the mechanism of RNA destabilization by TDP43, (ii) categorize the impact of RNA destabilization on protein translation and RNA homeostasis; and (iii) evaluate the therapeutic potential of two promising genetic modifiers, UPF1 and YTHDF2, for their ability to restore RNA homeostasis and extend neuronal survival in human neuron models of ALS and FTLD-TDP. These goals are mirrored by our long-term objectives: to crystalize the function of TDP43 in neurons and other cell types, and harness this information to devise effective neuroprotective strategies for ALS, FTLD-TDP and related TDP43-proteinopathies.

RNA衰变是RNA稳态的关键组成部分。转录活性细胞，例如神经元已经开发出复杂的途径来调节RNA更新并与RNA合成平衡。在最初的资金期间，我们发现了个体的RNA稳定性的广泛异常肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD），暗示功能障碍疾病发病机理中的RNA清除途径。我们还表明，其中许多异常可能是由TDP43的沉积（一种核RNA结合蛋白和剪接因子错误定位）概括 > 95％的ALS患者和最常见的FTLD亚型（FTLD-TDP）中的细胞质。在探测 TDP43沉积的下游后果，我们发现TDP43积累优先影响编码核糖体蛋白的mRNA剪接，导致内含子保留和mRNA过多不稳定。基于这些结果，我们假设TDP43在ALS中的错误定位和积累 FTLD-TDP破坏了核糖体蛋白编码的mRNA，损害翻译和干扰 RNA衰变机制依赖于主动翻译，包括废话介导的RNA衰变（NMD）。总之，这些现象将有望触发恶性循环最终在RNA和蛋白质中 dyshomeostasis，最终是神经变性。当前的建议基于初始资金的数据（i）阐明TDP43不稳定RNA的机制，（ii）对RNA的影响进行分类对蛋白质翻译和RNA稳态的不稳定；（iii）评估两个的治疗潜力有希望的遗传修饰符UPF1和YTHDF2恢复RNA稳态并扩展的能力 ALS和FTLD-TDP的人类神经元模型中的神经元存活。这些目标反映了我们的长期目的：将TDP43在神经元和其他单元类型中的功能结晶，并利用此信息为为ALS，FTLD-TDP和相关TDP43-蛋白质病设计有效的神经保护策略。