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Pathobiology and Treatment of the UBTF E210K Neuroregression Syndrome

UBTF E210K 神经退行综合征的病理学和治疗

基本信息

批准号：
10416149
负责人：
MARK S LEDOUX
金额：
$ 41.47万
依托单位：
UNIVERSITY OF MEMPHIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416149
关键词：
Affect Affinity Amino Acids Animal Model Apoptosis Apoptotic Architecture Awareness Behavioral Binding Bioavailable Biogenesis Biological Biological Assay Biological Models Brain Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Nucleolus Cell model Cells ChIP-seq Chromatin Chromatin Structure ClinVar Clinical Treatment Cognitive Cognitive deficits Complex DNA DNA Damage DNA Double Strand Break DNA Polymerase II DNA-Binding Proteins DNA-Directed RNA Polymerase Data Deterioration Disease Drosophila genus Embryo Exhibits Failure Fibroblasts Functional disorder Gene Expression Gene Silencing Genes Genetic Recombination Genetic Transcription Genetically Engineered Mouse Genome Genome Stability Goals HMGB Proteins Histones Human Label Maps Messenger RNA Metabolic Molecular Motor Mus Mutation Nature Nerve Degeneration Nervous System Physiology Neuraxis Neurologic Neurons Onset of illness Oral Pathway interactions Patients Polymerase Preclinical Testing Protein Isoforms Psoralens RNA Processing RNA, Ribosomal, 18S Recombinant DNA Recurrence Research Reverse Transcriptase Polymerase Chain Reaction Ribosomal RNA Ribosomes Role Site Stress Structure Switch Genes Syndrome Techniques Transcription Elongation Transcription Initiation Transgenic Organisms Up-Regulation cell type crosslink early childhood experimental study factor C genome-wide improved inhibitor/antagonist motor deficit motor disorder mouse model mutant nervous system disorder neuron loss pre-clinical promoter rRNA Genes transcription factor transcriptome sequencing

项目摘要

Recurrent de novo dominant mutations in UBTF (NM_014233.3:c.628G>A, p.Glu210Lys) were recently associated with a distinct neurological disorder dubbed the UBTF E210K neuroregression syndrome. UBTF exists as two major isoforms, UBTF1 and UBTF2. UBTF1 regulates ribosomal RNA (rRNA) transcription by RNA polymerase 1 (Pol I), whereas UBTF2 regulates mRNA transcription by RNA polymerase 2 (Pol II). UBTF c.628G>A results in the same amino acid change in both UBTF1 and UBTF2 (E210K). Disease onset is at 2.5 to 3 yrs and characterized by slow progression of global motor, cognitive and behavioral dysfunction. UBTF E210K modified binding to the rDNA promoter that affects formation of the preinitiation complex by the Pol1-specific TBP-complex SL1. Since both UBTF1 and UBTF2 contribute to DNA accessibility and genomic stability, the increased binding affinity of the UBTF E210K mutant to DNA could alter the interchange with histone chromatin that occurs when genes are switched off, potentially leaving the underlying DNA poorly protected. UBTF E210K fibroblasts show increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA double-strand breaks (DSBs), defective cell-cycle progression, and apoptosis. Ubtf-/- is early embryonic lethal in mice and transgenic expression of mutant human UBTF E210K in Drosophila neurons is also lethal. There are no known disease-modifying treatments for this disorder. Furthermore, we have not yet (i) clarified the relationships among increase expression of rRNA, DNA DSBs and cell-cycle abnormalities identified in patient fibroblasts, (ii) determined the mechanistic connections between nucleolar dysfunction and non-nucleolar DNA damage, or (iii) fully characterized a UBTF E210K mammalian model system. Our overall goals are to understand the mechanisms by which UBTF E210K causes progressive cellular dysfunction and develop a treatment for this devastating disorder. We hypothesize that Ubtf+/E210K mice will exhibit progressive motor and cognitive deficits, nucleolar abnormalities and apoptotic neuronal loss in association with accumulated DNA damage. Next, we will determine the effects of UBTF E210K on rRNA transcription, RNA processing, and RNA Pol I transcription elongation. Integrated analysis of ChIP-Seq and RNA-Seq will be used to determine the effects of UBTF E210K on chromatin structure and genome-wide gene expression. We will quantify the effects of UBTF E210K on rDNA, non-rDNA, and nucleolar structure. Psoralen cross-linking will be used to determine the ratio of active to inactive genes. ChIP-Seq mapping of γH2A.X will be used to map sites of DNA damage at the genome-wide level. Finally, we will test pre-clinical treatment of UBTF E210K cellular and animal models with orally-bioavailable and central nervous system penetrant Pol I inhibitors.

UBTf(NM_014233.3：C.628G&gt；A，p.Glu210Lys)中反复发生的从头显性突变是最近发生的与一种被称为UBTFE210K神经退行性综合征的独特神经疾病有关。UBTF 以两种主要亚型UBTF1和UBTF2存在。UBTF1通过以下途径调节核糖体RNA(RRNA)转录 RNA聚合酶1(Pol I)，而UBTF2通过RNA聚合酶2(Pol II)调节mRNA转录。 UBTFC.628G&gt；A导致UBTF1和UBTF2(E210K)的氨基酸变化相同。疾病的发病是年龄在2.5-3岁，以全球运动、认知和行为功能障碍进展缓慢为特征。 UBTFE210K修饰的与rDNA启动子的结合，影响通过 Pol1特异性TBP-复合体SL1。由于UBTF1和UBTF2对DNA可获得性和基因组都有贡献稳定性，UBTF E210K突变体与DNA结合亲和力的增加可以改变与DNA的相互作用当基因关闭时出现的组蛋白染色质，可能会使潜在的DNA质量变差受到保护。UBTF E210K成纤维细胞Pre-rRNA和18S rRNA、核仁表达增加异常，DNA双链断裂(DSB)数量显著增加，细胞周期缺陷进展和细胞凋亡。Ubtf-/-对小鼠早期胚胎致死作用及突变体的转基因表达人UBTFE210K在果蝇神经元中也是致命的。目前还没有已知的治疗疾病的方法来治疗这种疾病。此外，我们还没有(I)澄清增加表达之间的关系在患者成纤维细胞中发现的rRNA、DNA双链断裂和细胞周期异常，(Ii)确定了其机制核仁功能障碍与非核仁DNA损伤之间的联系，或(Iii)UBTF的完全特征 E210K哺乳动物模型系统。我们的总体目标是了解UBTF通过哪些机制 E210K会导致进行性细胞功能障碍，并开发一种治疗这种毁灭性疾病的方法。我们假设Ubtf+/E210K小鼠将表现出进行性运动和认知障碍，核仁异常以及与DNA损伤累积相关的神经细胞凋亡性丢失。接下来，我们将确定这些影响 UBTF E210K对rRNA转录、RNA加工和RNA Pol I转录延伸的影响。集成 ChIP-Seq和RNA-Seq分析将用于确定UBTFE210K对染色质的影响结构和全基因组的基因表达。我们将量化UBTF E210K对rDNA、非rDNA、和核仁结构。补骨脂素交联剂将用于确定活性基因与非活性基因的比例。 γH_2A.X的芯片序列图谱将被用来在全基因组水平上绘制DNA损伤的位置图。最后，我们将测试UBTF E210K细胞和动物模型的临床前治疗，口服生物利用度和中心神经系统渗透性POL I抑制剂。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HMG-boxes, ribosomopathies and neurodegenerative disease.

DOI：
10.3389/fgene.2023.1225832
发表时间：
2023
期刊：
FRONTIERS IN GENETICS
影响因子：
3.7
作者：
Moss, Tom;LeDoux, Mark S.;Crane-Robinson, Colyn
通讯作者：
Crane-Robinson, Colyn

Ribosomal DNA promoter recognition is determined in vivo by cooperation between UBTF1 and SL1 and is compromised in the UBTF-E210K neuroregression syndrome.

DOI：
10.1371/journal.pgen.1009644
发表时间：
2022-03
期刊：
PLoS genetics
影响因子：
4.5
作者：
Tremblay MG;Sibai DS;Valère M;Mars JC;Lessard F;Hori RT;Khan MM;Stefanovsky VY;LeDoux MS;Moss T
通讯作者：
Moss T

TOR2A Variants in Blepharospasm.

眼睑痉挛的 TOR2A 变体。

DOI：
10.5334/tohm.825
发表时间：
2023
期刊：
Tremor and other hyperkinetic movements (New York, N.Y.)
影响因子：
0
作者：
Saeirad S;LeDoux MS
通讯作者：
LeDoux MS

Presynaptic PRRT2 Deficiency Causes Cerebellar Dysfunction and Paroxysmal Kinesigenic Dyskinesia.

DOI：
10.1016/j.neuroscience.2020.08.034
发表时间：
2020-11-10
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Calame, Dylan J.;Xiao, Jianfeng;Khan, Mohammad Moshahid;Hollingsworth, T. J.;Xue, Yi;Person, Abigail L.;LeDoux, Mark S.
通讯作者：
LeDoux, Mark S.

No Neuron Operates in Isolation.

没有神经元是孤立运作的。