Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation

Hyunkyung Jeong, Florian Then, Thomas J. Melia, Joseph R. Mazzulli, Libin Cui, Jeffrey N. Savas, Cindy Voisine, Paolo Paganetti, Naoko Tanese, Anne C. Hart, Ai Yamamoto, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticle

258 Citations (Scopus)

Abstract

Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.

Original languageEnglish (US)
Pages (from-to)60-72
Number of pages13
JournalCell
Volume137
Issue number1
DOIs
StatePublished - Apr 3 2009

Fingerprint

Acetylation
Huntington Disease
Mutant Proteins
Degradation
Autophagy
Neurons
Neurodegenerative diseases
Corpus Striatum
Poisons
Post Translational Protein Processing
Neurodegenerative Diseases
Proteolysis
Lysine
Brain
Proteins
Autophagosomes

Keywords

  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jeong, Hyunkyung ; Then, Florian ; Melia, Thomas J. ; Mazzulli, Joseph R. ; Cui, Libin ; Savas, Jeffrey N. ; Voisine, Cindy ; Paganetti, Paolo ; Tanese, Naoko ; Hart, Anne C. ; Yamamoto, Ai ; Krainc, Dimitri. / Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation. In: Cell. 2009 ; Vol. 137, No. 1. pp. 60-72.
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Jeong, H, Then, F, Melia, TJ, Mazzulli, JR, Cui, L, Savas, JN, Voisine, C, Paganetti, P, Tanese, N, Hart, AC, Yamamoto, A & Krainc, D 2009, 'Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation', Cell, vol. 137, no. 1, pp. 60-72. https://doi.org/10.1016/j.cell.2009.03.018

Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation. / Jeong, Hyunkyung; Then, Florian; Melia, Thomas J.; Mazzulli, Joseph R.; Cui, Libin; Savas, Jeffrey N.; Voisine, Cindy; Paganetti, Paolo; Tanese, Naoko; Hart, Anne C.; Yamamoto, Ai; Krainc, Dimitri.

In: Cell, Vol. 137, No. 1, 03.04.2009, p. 60-72.

Research output: Contribution to journalArticle

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AU - Jeong, Hyunkyung

AU - Then, Florian

AU - Melia, Thomas J.

AU - Mazzulli, Joseph R.

AU - Cui, Libin

AU - Savas, Jeffrey N.

AU - Voisine, Cindy

AU - Paganetti, Paolo

AU - Tanese, Naoko

AU - Hart, Anne C.

AU - Yamamoto, Ai

AU - Krainc, Dimitri

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