小柯机器人

溶酶体K+通道调节帕金森氏病的发生
2021-01-28 14:03

美国宾夕法尼亚大学Dejian Ren、Kelvin C. Luk和Alice S. Chen-Plotkin团队合作的研究发现,生长因子激活的溶酶体K+通道调节帕金森氏病的发生。相关论文在线发表在2021年1月27日出版的《自然》杂志上。

研究人员发现了溶酶体K+通道复合物,该复合物被生长因子激活并由蛋白激酶B(AKT)门控,研究人员将其称为lysoKGF。LysoKGF由成孔蛋白TMEM175和AKT组成:TMEM175通过AKT的构象变化(而非催化活性)激活。 rs34311866是TMEM175的次要等位基也是其常见变体,其与帕金森氏病的患病风险增加和通道电流减少有关。减弱LysoKGF的功能使神经元容易受到压力诱导的损害,并加速病理性α-突触核蛋白的积累。

相比之下,次要等位基因rs3488217是TMEM175的另一个常见变体,与帕金森氏病的风险降低相关,其在细胞饥饿期间增强了LysoKGF的功能,并使神经元对损伤具有抵抗力。TMEM175的缺失会导致小鼠多巴胺能神经元丧失和运动功能的损害,而TMEM175功能丧失变体与帕金森氏病患者显著的认知和运动能力下降相关。

总之,该研究揭示了细胞外生长因子调节细胞内细胞器功能的途径,并建立了可靶向的机制,通过该机制TMEM175的常见变体增加了帕金森氏病的发生风险。

据了解,溶酶体具有基本的生理作用,之前研究表明其与帕金森氏症有关。但是,尚不清楚细胞外生长因子如何与细胞内的细胞器通讯以控制溶酶体功能。

附:英文原文

Title: A growth-factor-activated lysosomal K + channel regulates Parkinson’s pathology

Author: Jinhong Wie, Zhenjiang Liu, Haikun Song, Thomas F. Tropea, Lu Yang, Huanhuan Wang, Yuling Liang, Chunlei Cang, Kimberly Aranda, Joey Lohmann, Jing Yang, Boxun Lu, Alice S. Chen-Plotkin, Kelvin C. Luk, Dejian Ren

Issue&Volume: 2021-01-27

Abstract: Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson’s disease1,2,3,4,5. However, how extracellular growth factors communicate with intracellular organelles to control lysosomal function is not well understood. Here we report a lysosomal K+ channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoKGF. LysoKGF consists of a pore-forming protein TMEM175 and AKT: TMEM175 is opened by conformational changes in, but not the catalytic activity of, AKT. The minor allele at rs34311866, a common variant in TMEM175, is associated with an increased risk of developing Parkinson’s disease and reduces channel currents. Reduction in lysoKGF function predisposes neurons to stress-induced damage and accelerates the accumulation of pathological α-synuclein. By contrast, the minor allele at rs3488217—another common variant of TMEM175, which is associated with a decreased risk of developing Parkinson’s disease—produces a gain-of-function in lysoKGF during cell starvation, and enables neuronal resistance to damage. Deficiency in TMEM175 leads to a loss of dopaminergic neurons and impairment in motor function in mice, and a TMEM175 loss-of-function variant is nominally associated with accelerated rates of cognitive and motor decline in humans with Parkinson’s disease. Together, our studies uncover a pathway by which extracellular growth factors regulate intracellular organelle function, and establish a targetable mechanism by which common variants of TMEM175 confer risk for Parkinson’s disease.

DOI: 10.1038/s41586-021-03185-z

Source: https://www.nature.com/articles/s41586-021-03185-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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