中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (6): 1259-1260.doi: 10.4103/1673-5374.327340

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

溶酶体钙储存作为神经保护枢纽的新兴作用

  

  • 出版日期:2022-06-15 发布日期:2021-12-17

Emerging role of lysosomal calcium store as a hub of neuroprotection

Valentina Tedeschi, Agnese Secondo*   

  1. Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, “Federico II” University of Naples, Naples, Italy
  • Online:2022-06-15 Published:2021-12-17
  • Contact: Agnese Secondo, PhD, secondo@unina.it.
  • Supported by:
    The present work was supported by Progetto Speciale di Ateneo (CA.04_CDA_n_103 27.03.2019 to AS) and Programma di finanziamento linea-1 54_2020_FRA to AS. 

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摘要： Neural Regen Res：溶酶体治疗以自噬功能障碍为特征的神经退行性疾病
    酸性细胞器溶酶体可通过去除受损的细胞器和分解代谢产物来控制细胞消化。除了在细胞内降解途径中的典型作用外，溶酶体在自噬、免疫细胞信号、代谢和膜修复起主要作用。值得注意的是，这些必要功能中的大多数都依赖于 Ca2+。溶酶体现在被认为是负责 Ca2+ 储存和体内平衡的动态细胞器。溶酶体通道和转运蛋白不仅调节溶酶体离子稳态、膜电位、分解代谢物输出、膜运输和营养感应，而且还调节整个细胞 Ca2+ 稳态。溶酶体通道的功能障碍可能是许多溶酶体贮积病、其他代谢紊乱和一些神经退行性疾病的发病机制。溶酶体不断地与主要的细胞内钙库（包括内质网和线粒体）通信和交换离子。最新研究通过独特的内质网 Ca2+ 传感器 STIM1证明了这些微小细胞器和内质网之间的功能相互作用。细胞器 Ca2+ 稳态失调的溶酶体功能障碍可能是各种神经退行性疾病（包括肌萎缩侧索硬化症）的基础也就不足为奇了。最新研究已经证明位于溶酶体膜上并属于哺乳动物粘蛋白瞬时受体电位亚家族 TRPML1 或粘蛋白-1 的阳离子可渗透通道参与肌萎缩侧索硬化/帕金森病的发病机制-痴呆症复合体。暴露于蓝藻神经毒素 β-甲基氨基-L-丙氨酸的运动神经元中发生 TRPML1 的逐步下调，主要通过口服摄入与疾病病因有关。另一方面，TRPML1 的早期药理刺激可以通过抵消内质网应激和自噬损伤，有效地从 β-甲基氨基-L-丙氨酸毒性中拯救运动神经元。因此，建议通过 TRPML1 激活促进自噬可以代表探索肌萎缩侧索硬化症新有效药物的新治疗途径。 
    来自意大利那不勒斯费德里科二世大学的Agnese Secondo团队认为，TRPML1 是开启或关闭神经元自噬通量的方式。 TRPML1 刺激可促进肌萎缩侧索硬化症运动神经元的自噬，从而保持线粒体活性并防止内质网应激，而 TRPML1 下调可防止缺血性神经元死亡阻碍细胞器 Ca2+ 泄漏。溶酶体及其机制可能被认为是神经保护的枢纽，因为微小细胞器凭借与内质网的严格相互作用稳定全局离子平衡，以及它通过转录因子EB控制自噬过程。应致力于研究这一特定领域，以合成、表征和鉴定能够在药理学上调节 TRPML1 活性和溶酶体功能的新分子实体，从而治疗以自噬功能障碍为特征的神经退行性疾病。
   文章在《中国神经再生研究（英文版）》杂志2022年 6 月  6 期发表。
https://orcid.org/0000-0001-5054-4098 (Agnese Secondo) 

Abstract: Filled with more than 60 different types of hydrolases, the acidic organelle lysosome governs cellular digestion by removing damaged organelles and catabolic products (Xu and Ren, 2015). Beyond the canonical role in the intracellular degradative pathways, lysosome precedes nutrient sensing, autophagy, immune cell signaling, metabolism and membrane repair. Of note, most of these necessary functions are Ca2+-dependent. In this respect, lysosome is now being considered as a dynamic organelle deputed to Ca2+ storing and homeostasis (Patel and Muallem, 2011). Accordingly, lysosomal channels and transporters regulate not only lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing, but also the whole cellular Ca2+ homeostasis (Xu and Ren, 2015). Interestingly, dysfunction of lysosomal channels may underlie the pathogenesis of many lysosomal storage diseases, other metabolic disorders and some neurodegenerative diseases (Xu and Ren, 2015). Furthermore, lysosomes continuously communicate and exchange ions with the main intracellular calcium stores, including endoplasmic reticulum (ER) and mitochondria (Tedeschi et al., 2019a). In this respect, we have recently demonstrated a functional interplay between these tiny organelles and the ER through the unique ER Ca2+ sensor, STIM1 (Tedeschi et al., 2021). Therefore, it is not surprising that lysosomal dysfunction, determining organellar Ca2+ dyshomeostasis, may underlie various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). It has been recently postulated that channelopathy-like mechanisms may contribute to disease progression via pathological alterations in motor neuron intrinsic biophysical properties (Deardorff et al., 2021). In line with this view, we have demonstrated the involvement of a cation-permeable channel localized on lysosomal membrane and belonging to the mammalian mucolipin transient receptor potential (TRP) subfamily, TRPML1 or mucolipin-1, in the pathogenesis of amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), a Guamanian form of the disease (Tedeschi et al., 2019b). In this study we found that a progressive downregulation of TRPML1 occurs in motor neurons exposed to the cyanobacterial neurotoxin beta-methylamino-L-alanine (L-BMAA), mainly involved in the disease etiology through an oral ingestion (Dunlop et al., 2021). On the other hand, an early pharmacological stimulation of TRPML1 can efficiently rescue motor neurons from L-BMAA toxicity by counteracting ER stress and autophagy impairment (Tedeschi et al., 2019b). Therefore, we suggest that boosting autophagy via TRPML1 activation could represent a new therapeutic avenue to explore in searching for new effective drugs in ALS.