Abstract:
DYT1 dystonia is a debilitating neurological movement disorder, and it represents the most frequent and severe form of hereditary primary dystonia. There is currently no cure for this disease due to its unclear pathogenesis. In our previous study utilizing patient-specific motor neurons (MNs), we identified distinct cellular deficits associated with the disease, including a deformed nucleus, disrupted neurodevelopment, and compromised nucleocytoplasmic transport (NCT) functions. However, the precise molecular mechanisms underlying these cellular impairments have remained elusive. In this study, we revealed the genome-wide changes in gene expression in DYT1 MNs through transcriptomic analysis. We found that those dysregulated genes are intricately involved in neurodevelopment and various biological processes. Interestingly, we identified that the expression level of RANBP17, a RAN-binding protein crucial for NCT regulation, exhibited a significant reduction in DYT1 MNs. By manipulating RANBP17 expression, we further demonstrated that RANBP17 plays an important role in facilitating the nuclear transport of both protein and transcript cargos in induced human neurons. Excitingly, the overexpression of RANBP17 emerged as a substantial mitigating factor, effectively restoring impaired NCT activity and rescuing neurodevelopmental deficits observed in DYT1 MNs. These findings shed light on the intricate molecular underpinnings of impaired NCT in DYT1 neurons and provide novel insights into the pathophysiology of DYT1 dystonia, potentially leading to the development of innovative treatment strategies.
摘要:
DYT1肌张力障碍是一种使人衰弱的神经运动障碍,它代表了遗传性原发性肌张力障碍最常见和最严重的形式。由于其发病机理尚不清楚,目前尚无治愈方法。在我们先前利用患者特异性运动神经元(MNs)的研究中,我们发现了与疾病相关的明显的细胞缺陷,包括变形的细胞核,神经发育中断,和受损的核质转运(NCT)功能。然而,这些细胞损伤背后的精确分子机制仍然难以捉摸。在这项研究中,我们通过转录组学分析揭示了DYT1MNs基因表达的全基因组变化。我们发现这些失调的基因与神经发育和各种生物过程密切相关。有趣的是,我们确定了RANBP17的表达水平,RANBP17是一种对NCT调节至关重要的RAN结合蛋白,表现出DYT1MNs的显著降低。通过操纵RANBP17表达,我们进一步证明,RANBP17在促进蛋白质和转录物的核转运中起着重要作用。令人兴奋的是,RANBP17的过度表达是一个重要的缓解因素,有效恢复受损的NCT活动并挽救DYT1MNs中观察到的神经发育缺陷。这些发现揭示了DYT1神经元中受损NCT的复杂分子基础,并为DYT1肌张力障碍的病理生理学提供了新的见解。可能导致创新治疗策略的发展。DYT1肌张力障碍是一种使人衰弱的神经运动障碍,目前,由于其发病机制不清楚,目前尚无治愈方法。然而,患者神经元的不可接近性极大地阻碍了对这种疾病的研究进展。在这项研究中,我们从诱导多能干细胞(iPSCs)中产生了DYT1患者特异性神经元,并检测了全基因组基因表达的变化.我们已经确定了RANBP17,一个核运输监管机构,起到了实质性的缓解作用,有效挽救DYT1神经元中观察到的细胞缺陷。这些发现揭示了DYT1肌张力障碍中复杂的分子基础,并有可能导致创新治疗策略的发展。