Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human

Huynh, Duong P.; Figueroa, Karla P.; Hoang, Nam V.; Pulst, Stefan M.

doi:10.1038/79162

Cited by 302 publications

(273 citation statements)

References 49 publications

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“…Afterwards, cells were incubated with PBS containing 0.05% Triton X-100 for 15 minutes and blocked in PBS supplemented with 3% BSA for 30 minutes. Subsequently, cells were incubated for double-staining with primary antibodies directed against PABP (1 : 400, Abcam) and ATX2 (1 : 300, named SCA2B by Huynh et al 12 ) for one hour at RT. After incubation with the respective secondary antibody conjugated to Cy3 or FITC, respectively, (1 : 400, Dianova), cells were washed with PBS and nuclei were stained with 4 0 ,6-diamidine-2-phenylindoledihydrochloride (DAPI, Sigma).…”

Section: Confocal Microscopymentioning

confidence: 99%

“…10 In contrast, formation of intranuclear inclusions has not been observed in primarily degenerating Purkinje cells in the cerebellum and brainstem of SCA2 patients. 11,12additional evidence that intranuclear aggregates might not be obligatory for pathogenesis in SCA2. The expression of ATX2 with an expanded polyglutamine stretch resulted in the disruption of Golgi morphology, thus, rather linking cell death and stability of the Golgi complex.…”

Section: Introductionmentioning

confidence: 99%

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An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

Ralser

Albrecht

Nonhoff

et al. 2005

Journal of Molecular Biology

132

145

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Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by a trinucleotide expansion in the SCA2 gene, encoding a polyglutamine stretch in the gene product ataxin-2 (ATX2), whose cellular function is unknown. However, ATX2 interacts with A2BP1, a protein containing an RNA-recognition motif, and the existence of an interaction motif for the C-terminal domain of the poly(A)-binding protein (PABC) as well as an Lsm (Like Sm) domain in ATX2 suggest that ATX2 like its yeast homolog Pbp1 might be involved in RNA metabolism. Here, we show that, similar to Pbp1, ATX2 suppresses the petite (pet K ) phenotype of Dmrs2 yeast strains lacking mitochondrial group II introns. This finding points to a close functional relationship between the two homologs. To gain insight into potential functions of ATX2, we also generated a comprehensive protein interaction network for Pbp1 from publicly available databases, which implicates Pbp1 in diverse RNA-processing pathways. The functional relationship of ATX2 and Pbp1 is further corroborated by the experimental confirmation of the predicted interaction of ATX2 with the cytoplasmic poly(A)-binding protein 1 (PABP) using yeast-2-hybrid analysis as well as co-immunoprecipitation experiments. Immunofluorescence studies revealed that ATX2 and PABP co-localize in mammalian cells, remarkably, even under conditions in which PABP accumulates in distinct cytoplasmic foci representing sites of mRNA triage.

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Section: Confocal Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

Ralser

Albrecht

Nonhoff

et al. 2005

Journal of Molecular Biology

132

145

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“…PCR was carried out with the primer pair 1052A and 1190B (Huynh et al, 2000) and Taq DNA polymerase (Promega). Conditions were: 1 min 951C, 5 cycles of 951C for 45 s, 651C for 30 s, 701C for 1 min, followed by 30 cycles of 951C for 45 s, 601C for 30 s and 701C for 1 min.…”

Section: Rt-pcrmentioning

confidence: 99%

“…SCA2 is a hereditary neurodegenerative disease correlated with the expansion of a CAG stretch in patient DNA. The expansion results in an extended polyglutamine tract of ataxin-2, a highly basic protein with an apparent molecular mass of 145 kDa (Huynh et al, 2000) and unknown wild-type function. SCA2 is mainly characterized by loss of pontine and olivary nuclei and of Purkinje cells in the cerebellum (Estrada et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Ataxin-2 promotes apoptosis of human neuroblastoma cells

et al. 2003

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Neuroblastoma is a highly heterogeneous tumor of young children. Although many advances have been made towards understanding the molecular mechanisms dictating the phenotypic heterogeneity, the prognosis of children with neuroblastoma, particularly of progressively growing variants, has remained dire. About 10% of neuroblastomas regress spontaneously, probably by apoptosis, while another 20% have amplified the MYCN gene resulting in a poor prognosis. In pursuit of identifying cell deathassociated genes in neuroblastoma, we encountered the SCA2 gene, coding for ataxin-2, as an important player. Here, we report that enforced expression of wild-type ataxin-2, but not of mutant ataxin-2, sensitizes neuroblastoma cells for apoptosis. In line with this, higher levels of ataxin-2 were detected in apoptotic cells compared to nonapoptotic cells. Neuroblastoma tumors with amplified MYCN contain significantly less ataxin-2 protein than tumors without amplified MYCN. Collectively, our data suggest that ataxin-2 has an important role in regulating the susceptibility of neuroblastoma cells to apoptotic stimuli in vitro and in vivo.

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“…ITPR1 is highly expressed in Purkinje cells and is involved in calcium handling by regulating calcium release from the endoplasmic reticulum. Mutant ataxin‐2 caused an exaggerated calcium release from endoplasmic reticulum with increased cell death in Purkinje cells isolated from mutant ataxin‐2 transgenic mice,25 a model expressing full length polyglutamine‐expanded ataxin‐2 (Q58) targeted to Purkinje cells 18…”

Section: Protein and Its Functionmentioning

confidence: 99%

The Multiple Faces of Spinocerebellar Ataxia type 2

Antenora

Rinaldi

Roca

et al. 2017

Ann Clin Transl Neurol

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Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

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Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human

Cited by 302 publications

References 49 publications

An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

Ataxin-2 promotes apoptosis of human neuroblastoma cells

The Multiple Faces of Spinocerebellar Ataxia type 2

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