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首页> 外文期刊>Science Signaling >Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP
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Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP

机译：Niche衍生的层蛋白-511促进中脑多巴胺能神经元生存和通过yap分化

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摘要

Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms controlling the survival of mDA neurons. We found that the extracellular matrix protein laminin-511 (LM511) promoted the survival and differentiation of mDA neurons. LM511 bound to integrin alpha_3beta_n and activated the transcriptional cofactor YAP. LM511-YAP signaling enhanced cell survival by inducing the expression of the microRNA miR-130a, which suppressed the synthesis of the cell death-associated protein PTEN. In addition, LM511-YAP signaling increased the expression of transcription factors critical for mDA identity, such as LMX1A and PITX3, and prevented the loss of mDA neurons in response to oxidative stress, a finding that warrants further investigation to assess therapeutic potential for PD patients. We propose that by enhancing LM511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies.
机译：帕金森病（PD）是一种神经变性障碍，其中中脑中的多巴胺能神经元（MDA神经元）的丧失导致电机控制和功能的逐渐丧失。使用胚胎和MDA神经元，来自小鼠的中脑组织，以及分化的人神经干细胞，我们研究了控制MDA神经元存活的机制。我们发现细胞外基质蛋白层蛋白-511（LM511）促进了MDA神经元的存活率和分化。 LM511绑定到整合素Alpha_3beta_n并激活转录辅因子yap。 LM511-YAP通过诱导MicroRNA miR-130a的表达来引起细胞存活，这抑制了细胞死亡相关蛋白PTEN的合成。此外，LM511-YAP信号传递增加了对MDA同一性至关重要的转录因子的表达，例如LMX1A和PITX3，并阻止响应于氧化应激的MDA神经元的丧失，这是认证进一步调查评估PD患者治疗潜力的发现。我们提出通过增强LM511-YAP信号传导，可以防止PD中的MDA神经元变性或增强MDA神经元的存活在细胞替代疗法中。

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  • 来源
    《Science Signaling》 |2017年第493期|共11页
  • 作者

    Dawei Zhang; Shanzheng Yang; Enrique M. Toledo; Daniel Gyllborg; Carmen Salto; J. Carlos Villaescusa; Ernest Arenas;

  • 作者单位

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

    Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Instituted Stockholm SE-17177 Sweden;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
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