Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
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DOI：
10.1016/j.scr.2019.101504
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发表时间：
2019-08-01
影响因子：
1.2
通讯作者：
Paulson, Henry L.
中科院分区：
文献类型：
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作者：
Moore, Lauren R.;Keller, Laura;Paulson, Henry L.
脊髓小脑性共济失调3型（SCA 3）是一种致命的迟发性神经退行性疾病，其特征在于脑干、小脑、脊髓和黑质的选择性神经病理学。在这里，我们报告了第一个NIH批准的人胚胎干细胞（hESC）系来自一个胚胎窝藏SCA 3突变。被称为SCA 3-hESC，该细胞系对于ATXN 3基因中编码多聚谷氨酰胺的突变CAG重复扩增是杂合的。我们在从干细胞到皮质神经元的所有分化阶段观察到人类疾病的相关分子标志，包括强大的ATXN 3聚集和蛋白质质量控制机制关键组分的表达改变。此外，SCA 3-hESC表现出突变体ATXN 3的核积累并形成p62阳性侵袭体。最后，反义寡核苷酸介导的ATXN 3减少显着抑制侵略形成。SCA 3-hESC细胞系提供了一种独特且高度相关的人类疾病模型，具有很强的潜力来促进对SCA 3疾病机制的理解，并促进对SCA 3候选疗法的评估。
Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3.