CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity

Hanseok Seok Ko, Rachel Bailey, Wanli Smith, Zhaohui Liu, Joo Ho Shin, Yun Il Lee, Yong Jie Zhang, Haibing Jiang, Christopher A Ross, Darren J. Moore, Cam Patterson, Leonard Petrucelli, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

Abstract

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, ubiquitinates, 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.

Original languageEnglish (US)
Pages (from-to)2897-2902
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number8
DOIs
StatePublished - Feb 24 2009

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Ubiquitination
Leucine
Phosphotransferases
Parkinson Disease
tanespimycin
Mutation
Proteins
leucine-rich repeat proteins
Ubiquitin-Protein Ligases
Poisons
Ubiquitin
Cell Survival

Keywords

  • LRRK2
  • Parkinson's disease
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • General

Cite this

CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. / Ko, Hanseok Seok; Bailey, Rachel; Smith, Wanli; Liu, Zhaohui; Shin, Joo Ho; Lee, Yun Il; Zhang, Yong Jie; Jiang, Haibing; Ross, Christopher A; Moore, Darren J.; Patterson, Cam; Petrucelli, Leonard; Dawson, Ted M; Dawson, Valina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 8, 24.02.2009, p. 2897-2902.

Research output: Contribution to journalArticle

Ko, Hanseok Seok ; Bailey, Rachel ; Smith, Wanli ; Liu, Zhaohui ; Shin, Joo Ho ; Lee, Yun Il ; Zhang, Yong Jie ; Jiang, Haibing ; Ross, Christopher A ; Moore, Darren J. ; Patterson, Cam ; Petrucelli, Leonard ; Dawson, Ted M ; Dawson, Valina. / CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 8. pp. 2897-2902.
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AU - Lee, Yun Il

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AU - Jiang, Haibing

AU - Ross, Christopher A

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AU - Petrucelli, Leonard

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AU - Dawson, Valina

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AB - 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, ubiquitinates, 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.

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