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.

项目摘要 RNA聚合酶（POL）III合成了丰富的非编码RNA，例如tRNA，5S rRNA，u6 snRNA 以及参与基本细胞过程的7SL RNA，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具有重要作用，但POL III中的突变可以具有 POL III的患者证明了对中枢神经系统（CNS）的选择性作用。相关的白细胞营养不良。引起这种常染色体隐性神经退行性疾病的突变已经是在五个不同的具有疾病发作的五个不同的Pol III亚基中发现，在幼儿时期最常发生。 pol iii- 相关的白细胞营养不良通常是一种降低疾病，尽管患者都有两者范围神经和非神经学缺陷。神经系统缺陷通常包括与认知和运动功能，共济失调和小脑萎缩的逐步下降。非神经学缺陷可能包括减小，近视和内分泌异常。对疾病机制的理解目前缺乏这些临床特征的基础，并且治疗仅限于姑息治疗。一个在这两个方面的进步障碍是没有该疾病的动物模型。但是，最近的工作导致了与Pol III相关的白细胞营养不良的小鼠模型，该模型概括了临床特征的子集。 POLR3A中的致病突变的条件敲击，该突变编码最大 POL III亚基，特别是在中枢神经系统中表达寡聚2的细胞中，导致降低生长，神经行为大脑和脊髓多个区域中的缺陷和低切除。此外，电子显微镜除了分析少突胶质细胞群和特定蛋白质标记的分析外，还确定了两个有助于疾病发病机理的不同机制：少突胶质细胞的有缺陷分化前体细胞（OPC）和成熟少突胶质细胞（OLS）的功能有缺陷。然而，分子发病机理的机制仍然很差。为了促进这方面的理解，长期这项工作的术语目标是确定在OPC和OLS中如何更改POL III转录组突变小鼠并检查这些变化对蛋白质合成和蛋白质组的后果 OPC和OLS以及髓磷脂的脂肪组。此外，我们将测试一个模型，以抑制pol III的遗传抑制小鼠中相关的白细胞营养型表型。这些研究将共同告知Pol III如何减少转录会干扰少突根发生和髓鞘形成，产生重要的机械见解，A 潜在的治疗方法可能使与POL III相关的白细胞营养不良患者受益。