A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes.
A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes.
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DOI：
10.1007/s12035-021-02610-8
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发表时间：
2022-01
影响因子：
5.1
通讯作者：
Hübener-Schmid J
中科院分区：
文献类型：
--
作者：
Haas E;Incebacak RD;Hentrich T;Huridou C;Schmidt T;Casadei N;Maringer Y;Bahl C;Zimmermann F;Mills JD;Aronica E;Riess O;Schulze-Hentrich JM;Hübener-Schmid J
脊髓小脑性共济失调3型是世界范围内最常见的常染色体显性遗传性共济失调，由Ataxin-3基因CAG重复扩增导致相应蛋白中聚谷氨酰胺（polyQ）扩增引起。该疾病的特点是受影响的大脑区域发生神经病理、表型和特异性转录变化。到目前为止，还没有一种小鼠模型可以代表这种疾病的所有不同方面，但对更好地理解这种疾病的病理机制是非常必要的。在这里，我们描述了一种新的Ataxin-3敲入小鼠模型，通过生化、行为和转录组学方法表达了小鼠Ataxin-3位点上304个CAACAGs的杂合或纯合扩增。我们将新敲入模型的神经病理学和行为学特征与在SCA3研究中主要使用的YAC84Q小鼠模型进行了比较。此外，我们比较了SCA3敲入小鼠和死后SCA3患者小脑样本中发现的转录变化。这种新型敲入小鼠的特点是在小鼠Ataxin-3蛋白中表达polyq扩增，导致聚集形成，特别是在SCA3患者已知易感的大脑区域，以及浦肯野细胞的损伤。随着这些神经病理变化，小鼠表现出体重减轻，步态和平衡不稳定。小脑组织的转录组学分析揭示了年龄依赖性的差异表达，丰富了髓鞘性少突胶质细胞的基因。将这些变化与SCA3患者小脑组织中发现的变化进行比较，我们发现了差异表达基因的重叠，指出与髓鞘和髓鞘少突胶质细胞相关的几个基因中类似的基因表达紊乱。在线版本包含补充材料，可在10.1007/s12035-021-02610-8获得。
Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes. The online version contains supplementary material available at 10.1007/s12035-021-02610-8.
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影响因子：
3.5
作者：
Huebener, Jeannette;Weber, Jonasz Jeremiasz;Huu Phuc Nguyen
通讯作者：
Huu Phuc Nguyen
影响因子：
5.2
作者：
Hentrich, Thomas;Wassouf, Zinah;Schulze-Hentrich, Julia M.
通讯作者：
Schulze-Hentrich, Julia M.
影响因子：
4.5
作者：
Damrath, Ewa;Heck, Melanie V.;Auburger, Georg
通讯作者：
Auburger, Georg
影响因子：
5.3
作者：
Bichelmeier, Ulrike;Schmidt, Thorsten;Riess, Olaf
通讯作者：
Riess, Olaf
影响因子：
5.6
作者：
Jazurek-Ciesiolka, Magdalena;Ciesiolka, Adam;Fiszer, Agnieszka
通讯作者：
Fiszer, Agnieszka