Repeat associated neurodegeneration in CANVAS

摘要： 小脑性共济失调合并神经病和前庭反射不全综合征(Canvas)是一种起病晚、发病慢的疾病 进行性和隐性遗传性共济失调，特征为前庭、小脑和躯体感觉 损伤和小脑变性，导致严重的发病率和早期死亡。画布是 由复制的第二内含子内的双等位、非参考、五聚体AAGGG重复扩展引起 家族性和散发性画布中的因子复合物亚单位1(Rfc1)基因，以及相当一部分 所有迟发性退行性共济失调和感觉神经元病。控制组平均拥有11个AAAAG 在这个座位上重复，在帆布患者中被400-2000个AAGGG重复取代。这个 这种重复扩张导致神经变性的机制(S)尚不清楚。当画布展示时 这是一种隐性的遗传方式，迄今为止的研究表明，Rfc1的表达不受重复的影响 扩张。这种扩增有可能在两种不同的链特定背景下致病。在……上面 正义链，(AAGGG)n重复位于AluSx3转座元件的Poly(A)尾部，而 反义链(CCCTT)n重复位于Rfc1的大的第二内含子区域。这样做的目的是 建议是定义这些重复元件导致神经退行性变的机制 在帆布上。为了实现这一点，我们将结合使用患者衍生的ipsc模型和研究。 利用表达重复序列的记者来研究扩展的重复序列在两种内源背景下的情况 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素的潜力 直接引起毒性。综上所述，这些研究将提供所需的关键信息，以确定近端 画布内神经元毒性和神经退行性变的机制(S)和途径-关键 开发与疾病相关的疗法所需的第一步。

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.