Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells

IF 5.1 2区医学 Q1 NEUROSCIENCES Neurobiology of Disease Pub Date : 2024-09-20 DOI:10.1016/j.nbd.2024.106673

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown.

To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.

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扩增的 ATXN1 改变了从诱导多能干细胞分化而来的 SCA1 人类运动神经元的转录和钙信号转导。

脊髓小脑共济失调 1 型（SCA1）是一种显性遗传的致死性神经退行性疾病，由 ATAXIN-1 （ATXN1）基因中 CAG 重复序列的异常扩增引起。病理学研究发现，脑干和脊髓中的运动神经元（MNs）功能障碍和丧失，被认为会影响 SCA1 患者的吞咽和呼吸，从而导致过早死亡。然而，MN发病的分子和细胞机制仍然未知。为了研究人类MN的SCA1发病机制，我们将来自SCA1患者及其未受影响的兄弟姐妹的诱导多能干细胞（iPSC）分化为MN。我们检测了SCA1 MNs的祖细胞增殖、神经元生长、自发和谷氨酸诱导的钙离子活性，以研究发病的细胞机制。然后利用 RNA 测序来确定 iPSC 衍生的 MN 祖细胞（pMNs）和 MNs 中可能导致 SCA1 MNs 功能变化的转录改变。我们发现，SCA1 MNs 中的自发钙活性和诱发钙活性明显降低，并确定了钙信号调控基因的失调。这些结果表明，扩增的 ATXN1 会导致人类 MN 的钙信号功能失调。

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来源期刊

Neurobiology of Disease 医学-神经科学

CiteScore

11.20

自引率

3.30%

发文量

270

审稿时长

76 days

期刊介绍： Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.