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.

摘要： 小脑性共济失调伴神经病和前庭反射消失综合征（CANVAS）是一种迟发性、缓慢性、 以前庭、小脑和躯体感觉为特征的进行性和复发性遗传性共济失调 损伤和小脑变性，导致显著的发病率和早期死亡率。画布是 由复制的第二内含子内的双等位基因、非参照、五聚体AAGGG重复扩增引起 因子复合物亚基1（RFC 1）基因在家族性和散发性CANVAS，以及一个显着的分数， 都是迟发性退行性共济失调和感觉神经元病对照组平均具有11个AAAAG 在CANVAS患者中，该基因座上的重复被400-2000个AAGGG重复取代。的 这种重复扩增引起神经变性的机制是未知的。当帆布展示出 一种隐性遗传模式，迄今为止的研究表明，RFC 1的表达不受重复的影响， 扩展。在两种不同的链特异性背景下，该扩展具有致病性的潜力。对 有义链，（AAGGG）n重复序列位于一个NSx 3转座因子的poly（A）尾内，而 反义链（CCCTT）n重复位于RFC 1的大的第二内含子区域内。这个目标 一个建议是确定这些重复元件促进神经退行性变的机制 在CANVAS。为了实现这一目标，我们将使用患者来源的iPSC模型与研究相结合。 使用重复表达报告基因在其内源性背景下研究扩增的重复序列， 因为在容易操作的分析系统中，这将允许我们定义这些重复元件的潜力， 直接引起毒性。总之，这些研究将提供定义近端 CANVAS中神经元毒性和神经变性的机制和途径-一个关键的 这是开发疾病相关疗法所需的第一步。