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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity
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CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity

机译:CHIP调节富含亮氨酸的重复激酶2泛素化,降解和毒性

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摘要

Mutation in leucine-rich repeat kinase-2 (LRRK2) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiq-uitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.
机译:富含亮氨酸的重复激酶2(LRRK2)中的突变是迟发性帕金森氏病(PD)的最常见原因。尽管大多数PD是散发的,但有些是遗传的,包括由LRRK2突变引起的。因为这些突变可能与功能的毒性增加有关,所以控制LRRK2的表达可能会降低其细胞毒性。在这里,我们显示HSP70相互作用蛋白(CHIP)的羧基末端结合,泛素化并促进LRRK2泛素蛋白酶体降解。 CHIP的过表达保护和击倒CHIP会加剧由突变LRRK2介导的毒性。此外,HSP90与LRRK2形成复合物,并且17AAG对HSP90伴侣活性的抑制导致LRRK2的蛋白酶体降解,从而导致细胞活力增强。因此,增加CHIP E3连接酶活性和阻断HSP90伴侣活性可以预防LRRK2的有害作用。这些发现指出了LRRK2相关PD的潜在治疗选择。

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    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224;

    Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Sotomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Division of Cardiology, University of North Carolina, Chapel Hill, NC 27599;

    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224;

    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Sotomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Sotomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    LRRK2; parkinson's disease; proteasome; ubiquitin;

    机译:LRRK2;帕金森氏病蛋白酶体泛素;

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