Roles of ataxin-2 in pathological cascades mediated by TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS)

Yoshihiro Nihei, Daisuke Ito, Norihiro Suzuki

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The RNA-binding proteins TDP-43 and Fused in Sarcoma (FUS) play central roles in neurodegeneration associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Both proteins are components of messenger ribonucleoprotein (mRNP) granules and show cytoplasmic mislocalization in affected tissues. Recently, ataxin-2 was identified as a potent modifier of TDP-43 toxicity in an RNA-dependent manner. This study investigated to clarify how ataxin-2 modifies the TDP-43 and FUS pathological pathway. The expression of cytoplasmic TDP-43, the 35-kDa C-terminal fragment (TDP-p35f), and mutant FUS recruited ataxin-2 to mRNP granules, whereas increased ataxin-2 inhibited the mRNP granule formation of the 35-kDa C-terminal fragment and mutant FUS. A subcellular compartment analysis showed that the overexpressed ataxin-2 increased the cytoplasmic concentrations of both proteins, whereas it decreased their nuclear distributions. These data indicate that increased ataxin-2 impairs the assembly of TDP-43 and FUS into mRNP granules, leading to an aberrant distribution of RNA-binding proteins. Consequently, these sequences may exacerbate the impairment of the RNA-quality control system mediated by amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated RNA-binding proteins, which forms the core of the degenerative cascade.

Original languageEnglish
Pages (from-to)41310-41323
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number49
DOIs
Publication statusPublished - 2012 Nov 30

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DNA-Binding Proteins
Sarcoma
Frontotemporal Lobar Degeneration
RNA-Binding Proteins
Amyotrophic Lateral Sclerosis
RNA
Cytoplasmic Granules
Quality Control
Quality control
Toxicity
Ataxin-2
Proteins
Tissue
Control systems
messenger ribonucleoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Roles of ataxin-2 in pathological cascades mediated by TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS). / Nihei, Yoshihiro; Ito, Daisuke; Suzuki, Norihiro.

In: Journal of Biological Chemistry, Vol. 287, No. 49, 30.11.2012, p. 41310-41323.

Research output: Contribution to journalArticle

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