Studies on RNA polymerase III-related leukodystrophy

RNA聚合酶III相关脑白质营养不良的研究

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 RNA 聚合酶 (Pol) III 合成丰富的非编码 RNA，如 tRNA、5S rRNA、U6 snRNA 和 7SL RNA 参与重要的细胞过程，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发挥着重要作用，但 Pol III 的突变可能会导致 Pol III 患者证明了对中枢神经系统 (CNS) 具有显着的选择性作用相关脑白质营养不良。导致这种常染色体隐性神经退行性疾病的突变已被证实在五个不同的 Pol III 亚基中发现了疾病最常见于幼儿期的发病情况。波尔 III- 相关脑白质营养不良通常是一种髓鞘形成不足疾病，尽管患者同时存在一系列症状神经性和非神经性缺陷。神经系统缺陷通常包括发育迟缓认知和运动功能进行性下降、共济失调和小脑萎缩。非神经功能缺损可能包括牙齿发育不全、近视和内分泌异常。了解疾病机制目前缺乏这些临床特征的基础，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，最近的工作已经建立了 Pol III 相关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 致病性突变的条件敲入，Polr3a 编码最大的 Pol III 亚基，特别是在 CNS 中表达 Olig2 的细胞中，会导致生长、神经行为减慢大脑和脊髓多个区域的缺陷和髓鞘形成不足。此外，电子显微镜通过对少突胶质细胞群和特定蛋白质标记物的分析，确定了两种导致疾病发病机制的不同机制：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）的功能缺陷。尽管如此，分子发病机制仍不清楚。为了加深对这方面的了解，长期这项工作的长期目标是确定 Pol III 转录组在 OPC 和 OL 中是如何改变的突变小鼠并检查这些变化对蛋白质合成和蛋白质组的影响 OPCs 和 OLs 以及髓磷脂的脂质组。此外，我们将测试 Pol III 基因抑制模型- 小鼠中相关的脑白质营养不良表型。总之，这些研究将告诉我们如何减少 Pol III 转录干扰少突胶质细胞发生和髓鞘形成，产生重要的机制见解，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。