中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (2): 240-241.doi: 10.4103/1673-5374.177727

• 观点:退行性病与再生 • 上一篇    下一篇

磷脂酰肌醇（3,5）P2代谢功能障碍可致神经退行性疾病？

  

  • 收稿日期:2015-11-16 出版日期:2016-02-15 发布日期:2016-02-15

New insights into the functions of PtdIns(3,5)P2 in the pathogenisis of neurodegenerative disorders

Fuminori Tsuruta   

  1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan
  • Received:2015-11-16 Online:2016-02-15 Published:2016-02-15
  • Contact: Fuminori Tsuruta, Ph.D.,tsuruta.fuminori.fn@u.tsukuba.ac.jp.
  • Supported by:

    We apologize to the many authors whose papers could not be cited due to space limitations. I would like to thank Dr. Ricardo Dolmetsch and the members of his laboratory for their helpful discussion, Drs. Sergiu Pasca, Yu Kigoshi, and Takuma Aihara for critical reading of this paper.

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摘要：

膜运输系统在神经系统中有着重要作用。一些膜蛋白通过合并，从质膜除去掺入的内吞结构形成早期内涵体。接着，这些蛋白通过内陷体界膜被分类进入腔空间，导致多泡体的形成。由于膜运输系统对神经元形态、发育和存活的调节是必需的，因此在这个领域研究得到的见解有助于我们深化对大脑的理解。最近，我们研究组报道了磷脂酰肌醇（3,5）P2功能的神经元新机制。之前，我们报道了通过电压门控钙通道CaV1.2表达调控保护兴奋性毒性细胞死亡，其中磷脂酰肌醇（3,5）P2发挥了重要作用。在神经元中，细胞内Ca 2+浓度是协调神经元活性的一个重要因素。事实上，我们的研究表明，谷氨酸浴的应用促进了质膜中的CaV1.2内化，导致溶酶体降解。由于许多神经退行性疾病与这两个膜运输和钙稳态有关，因此他们在研究中确定的机制可以为为什么不稳定的磷脂酰肌醇（3,5）P2代谢会导致神经退行性疾病，如为肌萎缩侧索硬化症和腓骨肌萎缩症提供重要线索。我们最近的研究报告表示PIKfyve可以介导神经细胞内溶酶体运动，并且磷脂酰肌醇中（3,5）P2在各种细胞功能中发挥重要作用。这一发现揭示了一种新颖的磷脂酰肌醇（3,5）P2功能，并提供了一系列关于磷脂酰肌醇（3,5）P2的代谢障碍导致神经变性疾病的重要线索。

Abstract:

The membrane trafficking system plays an important role in the nervous system. Some membrane proteins are removed from the plasma membrane by incorporation into endocytic structures, which become early endosomes. Next, these proteins are sorted into the luminal space by invagination of the endosomal limiting membrane, leading to the formation of multivesicular bodies (MVBs). MVBs are morphologically distinct from late endosomes that internally accumulate small membrane vesicles containing the cargo proteins. The formation of MVBs is catalyzed by the Endosomal sorting complex required for transport (ESCRT) complexes, ESCRT-I, ESCRT-II, and ESCRT-III. These complexes form a network that recruits mono-ubiquitinated proteins and drives their internalization into luminal vesicles of MVBs. Finally the fusion of MVBs with lysosomes delivers internal vesicles and cargo proteins into the lysosomal lumen, where they are degraded by lysosomal proteases and lipases. Since the membrane trafficking system is essential for the regulation of morphology, development, and survival of neurons, studies in this field give useful insights that contribute to our understanding of the brain. Recently, we have reported a novel mechanism that underlie PtdIns(3,5)P2 functions in neurons. Previously, we reported that PIKfyve-produced PtdIns(3,5)P2 play important roles in the protection of excitotoxic cell death via regulation of voltage-gated calcium channel, CaV1.2 expression. In neurons, intracellular Ca2+ concentration is an important factor to coordinate neuronal activity. Indeed, our studies have shown that bath glutamate application promotes the internalization of CaV1.2 from the plasma membrane, leading to lysosomal degradation. As many neurodegenerative disorders are implicated in both membrane trafficking and Ca2+ homeostasis, the mechanisms identified in our study may provide an important clue of why perturbed PtdIns(3,5)P2 metabolism causes neurodegeneration such as ALS and Charcot-Marie-Tooth disease.
In conclusion, our recent study has reported that PIKfyve mediates endolysosomal motility in neurons. PtdIns(3,5)P2 play important roles in a variety of cellular functions. It is also known that dysregulation of PtdIns(3,5)P2 metabolism causes neuromuscular disorders such as Charcot-Marie-Tooth disease and ALS. Thus, our finding shed light on a novel function of PtdIns(3,5)P2 and provide an important clue that links perturbed PtdIns(3,5)P2 metabolism to neurodegenerative disorders.