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： 小脑共济失调与神经病和前庭症综合症（画布）是一种晚期，慢慢发作 渐进式和隐性共济失调的特征是前庭，小脑和体感 障碍和小脑变性，导致明显的发病率和早期死亡率。画布是 由复制的第二个内含子内的生物素，非参考，五聚体Aaggg重复扩展引起 家族和零星画布中的因子复合物亚基1（RFC1）基因，以及很大一部分 所有晚期发作性共济失调和感觉神经疾病。控件平均拥有11个AAAAG 在该基因座的重复序列，在画布患者中被400-2000个aaggg重复替换。这 这种重复膨胀导致神经退行性的机制未知。画布展览 迄今为止的一种隐性继承模式，表明RFC1表达不受重复的影响 扩展。扩展具有在两个不同链特异性环境中具有致病性的潜力。在 感官链，（aaggg）n重复位于alusx3转座元件的py（a）尾巴中，而 反义链（CCCTT）n重复位于RFC1的大第二个内含子区域内。目标的目标 建议是定义这些重复元素有助于神经变性的机制 在画布中。为此，我们将使用患者来源的IPSC模型以及研究的组合 使用重复表达的记者还研究其内源环境中扩展的重复 在易于操纵的测定系统中，这将使我们能够定义这些重复元素的潜力 直接引起毒性。综上所述，这些研究将提供定义近端所需的关键信息 机制和途径是帆布内神经元毒性和神经退行性的基础的途径 - 关键 开发疾病相关疗法所需的第一步。