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

doi:10.1074/jbc.m112.398099

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.

Highlights

The pathological mechanism of the potent modifier of TDP-43 toxicity, ataxin-2, is unknown
Endogenous Ataxin-2 Is Localized in messenger ribonucleoprotein (mRNP) Granules Mediated by the amyotrophic lateral sclerosis (ALS)-linked Molecules TDP-43 and Fused in Sarcoma (FUS)—A recent study [13] and Fig. 1 show that the cytoplasmic RNA binding protein ataxin-2 is a component of cytoplasmic mRNP granules, stress granules (SGs), indicating that ataxin-2 is potentially involved in regulating and controlling mRNA degradation, stability, and translation via mRNP granules
We examined the distributions of other deletion series and found that all the deletion series were recruited to mutant FUS and TDP-p35f mRNP granules, indicating that multiple regions are involved in ataxin-2 assembly with mRNP granules induced by mutant FUS and TDP-p35f

Summary

Background

The pathological mechanism of the potent modifier of TDP-43 toxicity, ataxin-2, is unknown. 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. 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. 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. Our findings indicated that ataxin-2 leads to an aberrant distribution of RNA-binding proteins, such as TDP-43 and FUS, leading to the enhancement of RNA dysregulation, which forms the core of the ALS/FTLD-U degenerative cascade [8, 14]

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION