Department of Human Biology, University of Cape Town, South Africa.
Neuroscience Institute, University of Cape Town, South Africa.
PLoS One. 2021 Feb 24;16(2):e0247434. doi: 10.1371/journal.pone.0247434. eCollection 2021.
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the ATXN7 gene. Patients with this disease suffer from a degeneration of their cerebellar Purkinje neurons and retinal photoreceptors that result in a progressive ataxia and loss of vision. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, we have generated induced pluripotent stem cells (iPSCs) from a cohort of SCA7 patients in South Africa. First, we differentiated the SCA7 affected iPSCs into neurons which showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). We then performed electrophysiology on the SCA7 iPSC-derived neurons and found that these cells show features of functional aberrations. Lastly, we were able to differentiate the SCA7 iPSCs into retinal photoreceptors that also showed similar transcriptional aberrations to the SCA7 neurons. Our findings give technical insights on how iPSC-derived neurons and photoreceptors can be derived from SCA7 patients and demonstrate that these cells express molecular and electrophysiological differences that may be indicative of impaired neuronal health. We hope that these findings will contribute towards the ongoing efforts to establish the cell-derived models of neurodegenerative diseases that are needed to develop patient-specific treatments.
脊髓小脑性共济失调 7 型（SCA7）是一种遗传性神经退行性疾病，由 ATXN7 基因中的多聚谷氨酰胺重复扩展引起。患有这种疾病的患者小脑浦肯野神经元和视网膜光感受器退化，导致进行性共济失调和视力丧失。与许多神经退行性疾病一样，发病机制的研究受到缺乏相关疾病模型的阻碍。为此，我们从南非的一组 SCA7 患者中生成了诱导多能干细胞（iPSC）。首先，我们将 SCA7 受影响的 iPSC 分化为神经元，这些神经元表现出影响 STAGA（ATXN7 和 KAT2A）和热休克蛋白途径（DNAJA1 和 HSP70）组件的转录表型的证据。然后，我们对 SCA7 iPSC 衍生的神经元进行了电生理学研究，发现这些细胞表现出功能异常的特征。最后，我们能够将 SCA7 iPSC 分化为视网膜光感受器，这些光感受器也表现出与 SCA7 神经元相似的转录异常。我们的研究结果提供了关于如何从 SCA7 患者中获得 iPSC 衍生神经元和光感受器的技术见解，并表明这些细胞表达的分子和电生理学差异可能表明神经元健康受损。我们希望这些发现将有助于建立神经退行性疾病的细胞衍生模型的持续努力，这是开发针对患者的治疗方法所必需的。
