Studies on RNA polymerase III-related leukodystrophy

RNA聚合酶III相关脑白质营养不良的研究

• 批准号: 10735229
• 负责人: IAN M WILLIS
• 金额: $ 68.83万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735229
• 关键词: 7SL RNA; Adolescence; Affect; Affinity Chromatography; Animal Disease Models; Animal Model; Ataxia; Atrophic; Binding; Birth; Brain; Brain region; Cell physiology; Cells; Central Nervous System; Characteristics; Clinical; Clinical/Radiologic; Cognitive; Defect; Developmental Delay Disorders; Diagnosis; Disease; Disease model; Electron Microscopy; Endocrine; Enzymes; Eukaryota; Eukaryotic Cell; Exhibits; Fasting; Genetic Models; Genetic Suppression; Genetic Transcription; Goals; Growth; Hypodontia; Inherited; Knock-in; Knock-out; Knowledge; Longevity; Mitochondria; Molecular; Motor; Mus; Mutant Strains Mice; Mutation; Myelin; Myopia; Neurodegenerative Disorders; Neurologic; Neurologic Deficit; Oligodendroglia; Onset of illness; Palliative Care; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Polymerase; Population; Property; Protein Biosynthesis; Protein Secretion; Proteome; RNA; RNA Polymerase III; RNA Processing; RNA Splicing; Research; Ribosomal RNA; Ribosomes; Role; Spinal Cord; Syndrome; System; Testing; Therapeutic; Time; Tissues; Transfer RNA; Translating; Translations; U6 small nuclear RNA; Untranslated RNA; Work; autosome; base; biological adaptation to stress; brain magnetic resonance imaging; early childhood; genetic variant; healthspan; insight; leukodystrophy; lipidome; mouse model; myelination; neurobehavioral; novel; oligodendrocyte lineage; oligodendrocyte precursor; precursor cell; protein biomarkers; transcriptome

Project Summary RNA polymerase (Pol) III synthesizes abundant non-coding RNAs such as tRNA, 5S rRNA, U6 snRNA and 7SL RNA that are involved in essential cellular processes including protein synthesis, RNA processing and protein secretion. Despite the essential roles of these RNAs in all eukaryotic cells, mutations in Pol III can have remarkably selective effects on the central nervous system (CNS) as demonstrated by patients with Pol III- related leukodystrophy. Mutations causing this autosomal recessive neurodegenerative disease have been identified in five different Pol III subunits with disease onset occurring most often in early childhood. Pol III- related leukodystrophy is typically a hypomyelinating disorder although patients present with a range of both neurological and non-neurological deficits. Neurological deficits typically include developmental delay with a progressive decline in cognitive and motor function, ataxia and cerebellar atrophy. Non-neurological deficits may include hypodontia, myopia and endocrine abnormalities. An understanding of the disease mechanisms underlying these clinical characteristics is currently lacking and treatments are limited to palliative care. A significant barrier to progress on both these fronts has been the absence of an animal model of the disease. However, recent work has resulted in a mouse model of Pol III-related leukodystrophy that recapitulates a subset of clinical features. Conditional knock-in of pathogenic mutations in Polr3a, which encodes the largest Pol III subunit, specifically in Olig2-expressing cells in the CNS, leads to reduce growth, neurobehavioral deficits and hypomyelination in multiple regions of the brain and spinal cord. Moreover, electron microscopy along with an analysis of oligodendrocyte cell populations and specific protein markers has identified two distinct mechanisms contributing to disease pathogenesis: Defective differentiation of oligodendrocyte precursor cells (OPCs) and defective function of mature oligodendrocytes (OLs). Nevertheless, the molecular mechanisms of pathogenesis remain poorly characterized. To advance understanding in this regard, the long- term goals of this work are to determine how the Pol III transcriptome has been altered in OPCs and OLs in the mutant mice and to examine the consequences of these changes for protein synthesis and for the proteome of OPCs and OLs and the lipidome of myelin. Additionally, we will test a model for genetic suppression of Pol III- related leukodystrophy phenotypes in the mice. Together, these studies will inform how decreasing Pol III transcription interferes with oligodendrogenesis and myelination, yielding important mechanistic insights, and a potential therapeutic approach that may benefit patients with Pol III-related leukodystrophy.

项目摘要 RNA聚合酶(Pol)III合成丰富的非编码RNA，如tRNA、5S rRNA、U6 SnRNA 和7SL RNA，参与基本的细胞过程，包括蛋白质合成，RNA加工和 蛋白质分泌。尽管这些RNA在所有真核细胞中都扮演着重要的角色，但POL III的突变可能具有 Pol III-患者对中枢神经系统(CNS)的显著选择性作用 相关的脑白质营养不良。导致这种常染色体隐性遗传性神经退行性疾病的突变 在五个不同的POL III亚基中发现，发病最常发生在儿童早期。POL III- 相关性脑白质营养不良是一种典型的髓鞘功能减退障碍，尽管患者同时存在两种症状。 神经性和非神经性缺陷。神经缺陷通常包括发育迟缓和 认知和运动功能进行性下降，共济失调和小脑萎缩。非神经性缺陷 可能包括牙齿发育不良、近视和内分泌异常。对疾病发生机制的认识 目前缺乏这些临床特征，治疗仅限于姑息治疗。一个 在这两个方面取得进展的重大障碍是缺乏该疾病的动物模型。 然而，最近的工作导致了一种与Pol III相关的脑白质营养不良的小鼠模型，该模型概括了 临床特征的子集。POLR3A致病突变的条件性敲入，它编码了最大的 POL III亚单位，特别是在CNS中表达寡核苷酸的细胞中，导致生长、神经行为减少 在大脑和脊髓的多个区域出现缺陷和髓鞘减退。此外，电子显微镜 连同对少突胶质细胞群体和特定蛋白标记的分析一起确定了两个 疾病发病的不同机制：少突胶质细胞分化缺陷 前体细胞(OPC)和成熟少突胶质细胞(OL)功能缺陷。然而，分子 其发病机制尚不清楚。为了增进对这方面的了解，长期- 这项工作的学期目标是确定POLIII转录组在OPC和OL中是如何改变的 并检测这些变化对蛋白质合成和蛋白质组的影响。 OPC、OL和髓磷脂脂体。此外，我们将测试Pol III的基因抑制模型- 小鼠的相关脑白质营养不良表型。总而言之，这些研究将告诉我们，如何减少POLIII 转录干扰少突胶质细胞发生和髓鞘形成，产生重要的机制洞察力，并且 可能使Pol III相关脑白质营养不良患者受益的潜在治疗方法。