Repeat associated neurodegeneration in CANVAS

CANVAS 中重复相关的神经变性

• 批准号: 10536010
• 负责人: Peter K Todd
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536010
• 关键词: Ataxia; Atrophic; Autopsy; Basal Ganglia; Biological Assay; Brain region; CRISPR/Cas technology; Cells; Cerebellar Ataxia; Cerebellar Diseases; Cerebellar degeneration; Complex; DNA Transposable Elements; Defect; Development; Diffuse; Disease; Disease Progression; Disease model; Drosophila genus; Elements; Exhibits; Face; Genes; Genetic; Goals; Human; Impairment; Induced pluripotent stem cell derived neurons; Inheritance Patterns; Inherited; Introns; Lead; Length; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurons; Neuropathy; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pentanucleotide Repeats; Peptides; Peripheral; Pluripotent Stem Cells; Poly(A) Tail; Population; Prosencephalon; Proteins; Purkinje Cells; RNA; Reporter; Sensory; Syndrome; System; Technology; Testing; Therapeutic; Toxic effect; Translating; Translations; Trigeminal System; Work; base; cerebral atrophy; effective therapy; gain of function; induced pluripotent stem cell; loss of function; mortality; neuron loss; neuronal survival; neurotoxicity; novel; sensory neuropathy; somatosensory; therapeutic target; tool; transcriptome

Abstract: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive and recessively inherited ataxia characterized by vestibular, cerebellar, and somatosensory impairments and cerebellar degeneration that results in significant morbidity and early mortality. CANVAS is caused by a biallelic, non-reference, pentameric AAGGG repeat expansion within the second intron of replication factor complex subunit 1 (RFC1) gene in both familial and sporadic CANVAS, as well as a significant fraction of all late-onset degenerative ataxias and sensory neuronopathies. Controls possess an average of 11 AAAAG repeats at this locus, which is replaced with between 400-2000 AAGGG repeats in CANVAS patients. The mechanism(s) by which this repeat expansion causes neurodegeneration are unknown. While CANVAS exhibits a recessive pattern of inheritance, studies to date suggest that RFC1 expression is not impacted by the repeat expansions. The expansion has the potential to be pathogenic within two different strand-specific contexts. On the sense strand, the (AAGGG)n repeat sits within the poly(A) tail of an AluSx3 transposable element, while the antisense strand (CCCTT)n repeat sits within the large second intronic region of RFC1. The goal of this proposal is to define the mechanisms by which these repeat elements contribute to neurodegeneration in CANVAS. To accomplish this, we will use a combination of patient-derived iPSC models alongside studies using repeat-expressing reporters to investigate the expanded repeat within both its endogenous context as well as within easily manipulable assay systems that will allow us to define the potential of these repeat elements to elicit toxicity directly. Taken together, these studies will provide critical information needed to define the proximal mechanism(s) and pathways that underlie neuronal toxicity and neurodegeneration within CANVAS – a critical first step required for development of disease relevant therapeutics.

抽象的： 小脑性共济失调伴神经病和前庭无反射综合征 (CANVAS) 是一种迟发性、缓慢的疾病 以前庭、小脑和体感为特征的进行性和隐性遗传性共济失调 损伤和小脑变性导致显着的发病率和早期死亡。画布是 由复制的第二个内含子内的双等位基因、非参考、五聚体 AAGGG 重复扩增引起 家族性和散发性 CANVAS 中的因子复合体亚基 1 (RFC1) 基因，以及很大一部分 所有迟发性退行性共济失调和感觉神经病。控件平均拥有 11 AAAAG 该基因座上的重复序列在 CANVAS 患者中被 400-2000 个 AAGGG 重复序列取代。这 这种重复扩张导致神经变性的机制尚不清楚。在CANVAS展出的同时 隐性遗传模式，迄今为止的研究表明 RFC1 表达不受重复序列的影响 扩展。这种扩展有可能在两种不同的特定链环境中致病。在 有义链中，(AAGGG)n 重复序列位于 AluSx3 转座元件的 Poly(A) 尾内，而 反义链 (CCCTT)n 重复序列位于 RFC1 的第二大内含子区域内。此举的目标 提案是定义这些重复元件导致神经退行性变的机制 在画布中。为了实现这一目标，我们将结合使用源自患者的 iPSC 模型和研究 使用重复表达记者来调查其内源性背景下的扩展重复 就像在易于操作的分析系统中一样，这将使我们能够定义这些重复元件的潜力 直接引起毒性。总而言之，这些研究将提供定义近端所需的关键信息。 CANVAS 内神经元毒性和神经变性的机制和途径——一个关键 开发疾病相关疗法所需的第一步。