Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates

Yasushi Mitomi, Takao Nomura, Masaru Kurosawa, Nobuyuki Nukina, Yoshiaki Furukawa

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.

Original languageEnglish
Pages (from-to)34764-34775
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number41
DOIs
Publication statusPublished - 2012 Oct 5

Fingerprint

Agglomeration
Methionine
Oxidation
Neurodegenerative Diseases
Proteins
Huntington Disease
Post Translational Protein Processing
Neurodegenerative diseases
Hydrogen Peroxide
Copper
Ions
Molecules
Protein Aggregates

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates. / Mitomi, Yasushi; Nomura, Takao; Kurosawa, Masaru; Nukina, Nobuyuki; Furukawa, Yoshiaki.

In: Journal of Biological Chemistry, Vol. 287, No. 41, 05.10.2012, p. 34764-34775.

Research output: Contribution to journalArticle

Mitomi, Yasushi ; Nomura, Takao ; Kurosawa, Masaru ; Nukina, Nobuyuki ; Furukawa, Yoshiaki. / Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 41. pp. 34764-34775.
@article{d388f99f37df47c5963de926fb4bcc59,
title = "Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates",
abstract = "Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a {"}post-aggregation{"} modification is a relevant factor to regulate properties of protein aggregates.",
author = "Yasushi Mitomi and Takao Nomura and Masaru Kurosawa and Nobuyuki Nukina and Yoshiaki Furukawa",
year = "2012",
month = "10",
day = "5",
doi = "10.1074/jbc.M112.387035",
language = "English",
volume = "287",
pages = "34764--34775",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "41",

}

TY - JOUR

T1 - Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates

AU - Mitomi, Yasushi

AU - Nomura, Takao

AU - Kurosawa, Masaru

AU - Nukina, Nobuyuki

AU - Furukawa, Yoshiaki

PY - 2012/10/5

Y1 - 2012/10/5

N2 - Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.

AB - Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.

UR - http://www.scopus.com/inward/record.url?scp=84867267823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867267823&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.387035

DO - 10.1074/jbc.M112.387035

M3 - Article

C2 - 22891249

AN - SCOPUS:84867267823

VL - 287

SP - 34764

EP - 34775

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 41

ER -