Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study

Koyano, Shigeru; Uchihara, Toshiki; Fujigasaki, Hiroto; Nakamura, Ayako; Yagishita, Saburo; Iwabuchi, K

doi:10.1016/s0304-3940(99)00656-4

Cited by 121 publications

(102 citation statements)

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“…In this case, we did not observe any effect on the cellular P-body structures (Figure 4). Together, these experiments demonstrate that an elevated cellular ATXN2 level, as observed in SCA2 patients and some neuroblastomas (Huynh et al, 1999;Koyano et al, 1999;Wiedemeyer et al, 2003), can interfere with the presence of P-body structures. …”

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confidence: 58%

“…Moreover, elevated ATXN2 levels sensitize certain neuroblastoma cells for apoptosis (Huynh et al, 1999;Koyano et al, 1999;Wiedemeyer et al, 2003). Therefore, we set out to directly investigate whether an elevated level of normal or diseasecausing expanded ATXN2 protein would have an impact on the cellular P-body structures.…”

Section: Elevated Atxn2 Levels Interfere With Cellular P-body Structuresmentioning

confidence: 99%

“…Subsequently, we addressed what the resulting functional consequences of alterations in the intracellular ATXN2 concentration on these cellular structures would be, because enhanced levels of ATXN2 have been observed in Purkinje cells of humans with age and in Purkinje cells of SCA2 patients, indicating that alterations of intracellular ATXN2 may contribute to cellular dysfunction and could correlate with disease progression (Huynh et al, 1999;Koyano et al, 1999). Interestingly, changes in the cellular concentration of ATXN2 seem to have an impact on cancer as well.…”

Section: Molecular Biology Of the Cell 1392mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Moreover, the molecular mechanisms contributing to most of these disorders and particularly SCA2 are far from being understood. However, evidence exists that an accumulation of ATXN2, as observed in SCA2 brains, might contribute to cellular dysfunction and SCA2 pathogenesis (Huynh et al, 1999;Koyano et al, 1999).The biological function of ATXN2 is unknown, but evidence has been provided that ATXN2 is involved in the cellular RNA metabolism. Initially, ATXN2 was identified to interact with the protein A2BP1 (ATXN2 binding protein 1) that contains RNA recognition motifs (Shibata et al, 2000).…”

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Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

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Ralser

Welzel

et al. 2007

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Tight control of translation is fundamental for eukaryotic cells, and deregulation of proteins implicated contributes to numerous human diseases. The neurodegenerative disorder spinocerebellar ataxia type 2 is caused by a trinucleotide expansion in the SCA2 gene encoding a lengthened polyglutamine stretch in the gene product ataxin-2, which seems to be implicated in cellular RNA-processing pathways and translational regulation. Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage. We discovered that altered ataxin-2 levels interfere with the assembly of stress granules and cellular P-body structures. Moreover, ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, another stress granule component and a key factor for translational control. Thus, our data imply that the cellular ataxin-2 concentration is important for the assembly of stress granules and P-bodies, which are main compartments for regulating and controlling mRNA degradation, stability, and translation. INTRODUCTIONAn essential step in the control of global gene expression in eukaryotes is the regulation of mRNA translation and degradation. Shortening of the poly(A) tail is the initial step to trigger mRNA for decay in two major mRNA degradation pathways in eukaryotic cells (Bernstein and Ross, 1989;Peltz et al., 1991;Decker and Parker, 1994;Beelman and Parker, 1995). In one pathway, the deadenylated mRNA is degraded by a cytoplasmic protein complex, the exosome, consisting of a number of exonucleases with 3Ј-5Ј activity (Butler, 2002). In the other pathway, shortening of the poly(A) tail leads to the removal of the cap structure of the mRNA by the decapping proteins DCP1 and DCP2 facilitating 5Ј-3Ј degradation of the mRNA through the exoribonuclease XRN1 (Beelman and Parker, 1995;Butler, 2002). These proteins colocalize in discrete cytoplasmic foci in mammalian cells, termed processing bodies or P-bodies (also known as DCP1-or GW182-bodies), indicating that mRNA decay is restricted to distinct cytoplasmic compartments in mammalian cells (van Dijk et al., 2002;Cougot et al., 2004). The human protein CCR4, which is involved in mRNA deadenylation, the decapping stimulating LSm proteins LSm1-7, the DEAD/Hbox RNA helicase DDX6 (also known as RCK/p54), GW182, and Ge-1 are components of P-bodies (Bouveret et al., 2000;Eystathioy et al., 2002;Ingelfinger et al., 2002; LykkeAndersen, 2002;Cougot et al., 2004;Yu et al., 2005). Moreover, the RNA-associated protein 55, hEDC3, Hedls as well as factors of the RISC complex localize to P-bodies in mammalian cells (Fenger-Gron et al., 2005;Liu et al., 2005;Sen and Blau, 2005;Yang et al., 2006). P-bodies represent dynamic structures that are in an equilibrium with polysomes and contain nontranslating mRNA . Remarkably, recent work demonstrated that mRNA molecules entering P-bodies can a...

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confidence: 58%

Section: Elevated Atxn2 Levels Interfere With Cellular P-body Structuresmentioning

confidence: 99%

Section: Molecular Biology Of the Cell 1392mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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