Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo, Manuela Lima, Luis Pereira de Almeida, Hector Garcia-Moreno, Paola Giunti, Jeroen de Vries, Bart P van de Warrenburg, Judith van Gaalen, Marcus Grobe-Einsler, Berkan Koyak, Kathrin Reetz, Friedrich Erdlenbruch, Heike Jacobi, Jon Infante, Holger Hengel, Ludger Schöls, Thomas Klockgether, Olaf Rieß, Jeannette Hübener-Schmid
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Abstract

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease whose exact disease pathogenesis is not yet fully understood. We performed a genetic in-depth analysis of ataxin-2 (ATXN2), a gene that has already been described as a modulator of neurodegenerative diseases. We focused on the influence of an intermediate CAG repeat, a 9bp duplication (9bp), and isoform expression of ATXN2 on the pathogenesis of SCA3.Clinical and genetic data from a large European SCA3 cohort (total 390 probands) were analyzed. Fragment analyses were performed to determine the cytosine-adenine-guanine (CAG) repeat length and the 9bp duplication in ATXN2. RNA sequencing was performed on blood and cerebellum to evaluate ATXN2 isoform profile. Cell culture and SCA3 mice were used to investigate the influence of intermediate ATXN2 length on ataxin-3 protein abundance, aggregation, and cell viability.SCA3 carriers with an intermediate ATXN2 repeat presented a significant increase in non-ataxic symptoms. A greater age at onset and faster disease progression were found in SCA3 carriers with a 9bp duplication. Co-expression of ATXN2 and ATXN3 in cell models revealed an influence of ATXN2 on ataxin-3 abundance and aggregation patterns. Determination of soluble ATXN2 abundance demonstrated a significant genotype-independent reduction in mouse brain. Aggregate analyses indicated that ataxin-2 is not co-localized with ataxin-3-containing aggregates.Our comprehensive genetic study confirmed ATXN2 as a modulator of SCA3 pathogenesis, including onset and presence of clinical symptoms. For the first time, the ATXN2 isoform profile was compared in blood and cerebellar tissue, revealing a unique profile depending on the genotype and tissue. Here, a significant higher expression of ATXN2 splice variant type I in blood and significantly lower expression in cerebellar tissue were found compared to ATXN2 splice variant type II. Molecular and biochemical analyses in SCA3 mice and cell culture provide further evidence on mechanistic aspects, including differences in protein abundance and co-aggregation propensity. In summary, our study provides new insights into the modulatory effects of ATXN2 on SCA3 pathogenesis.

ATXN2中间CAG重复序列、9bp重复和选择性剪接对SCA3发病机制的影响。
脊髓小脑性共济失调3型(SCA3)是一种神经退行性疾病,其确切的发病机制尚不完全清楚。我们对ataxin-2 (ATXN2)进行了深入的遗传分析,该基因已被描述为神经退行性疾病的调节剂。我们重点研究了中间CAG重复、9bp重复(9bp)和ATXN2亚型表达对SCA3发病机制的影响。分析了来自欧洲大型SCA3队列(共390个先证者)的临床和遗传数据。片段分析测定ATXN2的胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复长度和9bp重复。对血液和小脑进行RNA测序,评估ATXN2亚型谱。通过细胞培养和SCA3小鼠研究中间ATXN2长度对ataxin-3蛋白丰度、聚集和细胞活力的影响。具有中间ATXN2重复序列的SCA3携带者出现非共济失调症状的显著增加。在具有9bp重复的SCA3携带者中,发现发病年龄更大,疾病进展更快。ATXN2和ATXN3在细胞模型中的共表达揭示了ATXN2对ataxin-3丰度和聚集模式的影响。可溶性ATXN2丰度的测定表明,在小鼠大脑中存在显著的基因型无关的减少。聚集分析表明,ataxin-2不与含有ataxin-3的聚集体共定位。我们的综合遗传学研究证实ATXN2是SCA3发病机制的调节剂,包括临床症状的发生和存在。首次比较了血液和小脑组织中的ATXN2亚型谱,揭示了依赖于基因型和组织的独特谱。与ATXN2剪接变体II型相比,ATXN2剪接变体I型在血液中的表达显著升高,而在小脑组织中的表达显著降低。SCA3小鼠和细胞培养的分子和生化分析提供了机制方面的进一步证据,包括蛋白质丰度和共聚集倾向的差异。总之,我们的研究为ATXN2在SCA3发病机制中的调节作用提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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