Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Byoung Il Bae; Makoto R. Hara; Matthew B. Cascio; Cheryl L. Wellington; Michael R. Hayden; Christopher A. Ross; Hyo Chol Ha; Xiao Jiang Li; Solomon H. Snyder; Akira Sawa

doi:10.1073/pnas.0511316103

Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Byoung Il Bae, Makoto R. Hara, Matthew B. Cascio, Cheryl L. Wellington, Michael R. Hayden, Christopher A. Ross, Hyo Chol Ha, Xiao Jiang Li, Solomon H. Snyder, Akira Sawa

School of Medicine

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.

Original language	English (US)
Pages (from-to)	3405-3409
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	9
DOIs	https://doi.org/10.1073/pnas.0511316103
State	Published - Feb 28 2006

Keywords

Huntington's disease
Polyglutamine
Siah

ASJC Scopus subject areas

General

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10.1073/pnas.0511316103

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abstract = "The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.",

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AU - Bae, Byoung Il

AU - Hara, Makoto R.

AU - Cascio, Matthew B.

AU - Wellington, Cheryl L.

AU - Hayden, Michael R.

AU - Ross, Christopher A.

AU - Ha, Hyo Chol

AU - Li, Xiao Jiang

AU - Snyder, Solomon H.

AU - Sawa, Akira

PY - 2006/2/28

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AB - The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.

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KW - Polyglutamine

KW - Siah

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Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Abstract

Keywords

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