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首页> 外文期刊>Nature >A growth-factor-activated lysosomal K～+channel regulates Parkinson's pathology
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A growth-factor-activated lysosomal K～+channel regulates Parkinson's pathology

机译：生长因子活化溶酶体K〜+通道调节帕金森病理学

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摘要

Lysosomes have fundamental physiological roles and have previously been implicated in Parkinsons disease(1-5). 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 lysoK(GF.) LysoK(GF) 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 Parkinsons disease and reduces channel currents. Reduction in lysoK(GF) function predisposes neurons to stress-induced damage and accelerates the accumulation of pathological alpha-synuclein. By contrast, the minor allele at rs3488217another common variant of TMEM175, which is associated with a decreased risk of developing Parkinsons diseaseproduces a gain-of-function in lysoK(GF) 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 Parkinsons 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 Parkinsons disease.
机译：溶酶体具有基本的生理作用，以前涉及帕金森病（1-5）。然而，细胞外生长因子如何与细胞内细胞器通信以控制溶酶体功能尚不清楚。在这里，我们报告了一种溶酶体K +通道复合物，其被生长因子激活并被蛋白质激酶B（AKT）所浇注的溶差（GF）葡萄蟾（GF）由孔隙形成蛋白TMEM175和AKT：TMEM175打开构象变化，但不是akt的催化活性。 RS34311866的次要等位基因是TMEM175中的常见变体，与发育帕金森病的风险增加，并减少了通道电流。溶差（GF）功能的还原促使神经元以应力诱导的损伤，加速病理α-突触核蛋白的积累。相比之下，TMEM175的RS3488217的次要等位基因在TMEM175中的其他常见变体，其与发育帕金森病的风险降低有关，在细胞饥饿期间，在溶差（GF）中的功能下降，并且能够使神经元抵抗损伤。 TMEM175的缺乏导致多巴胺能神经元和小鼠电机功能的损伤，并且TMEM175失去功能变量名义上与帕金森病的人类的认知和电机下降的加速率相关。我们的研究一起发现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TMEM175赋予帕金森病风险的常见变体的可算法机制。

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  • 来源
    《Nature》 |2021年第7850期|431-437|共7页
  • 作者

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

  • 作者单位

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

    Fudan Univ MOE Frontiers Ctr Brain Sci Sch Life Sci State Key Lab Med Neurobiol Shanghai Peoples R China;

    Univ Penn Perelman Sch Med Dept Neurol Philadelphia PA 19104 USA;

    Peking Univ Sch Life Sci IDG McGovern Inst Brain Res Beijing Peoples R China;

    Peking Univ Sch Life Sci IDG McGovern Inst Brain Res Beijing Peoples R China;

    Univ Penn Perelman Sch Med Ctr Neurodegenerat Dis Res Dept Pathol & Lab Med Philadelphia PA 19104 USA;

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

    Peking Univ Sch Life Sci IDG McGovern Inst Brain Res Beijing Peoples R China;

    Fudan Univ MOE Frontiers Ctr Brain Sci Sch Life Sci State Key Lab Med Neurobiol Shanghai Peoples R China;

    Univ Penn Perelman Sch Med Dept Neurol Philadelphia PA 19104 USA;

    Univ Penn Perelman Sch Med Ctr Neurodegenerat Dis Res Dept Pathol & Lab Med Philadelphia PA 19104 USA;

    Univ Penn Dept Biol Philadelphia PA 19104 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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