Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures

Skinner, Pamela J.; Koshy, Beena; Cummings, Christopher J.; Klement, Ivan A.; Helin, Kristian; Servadio, Antonio; Zoghbi, Huda Y.; Orr, Harry T.

doi:10.1038/40153

Cited by 512 publications

(373 citation statements)

References 26 publications

(24 reference statements)

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“…ATXN1 is an RNAbinding protein thought to act as a transcriptional repressor (Yue et al, 2001;Irwin et al, 2005). The expression of pathogenic ATXN1 protein carrying expanded tracts of polyQ results in Spinocerebellar Ataxia type 1 (SCA1), a disease that decimates cerebellar Purkinje cells and brain stem neurons (Skinner et al, 1997). Therefore, it is likely that HMGA1 might have a certain role in the development of the cerebellum, even though Hmga1-null mice do not show a gross impairment of the cerebellar functions.…”

Section: Discussionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

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Section: Discussionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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“…Experiments were carried out according to a protocol approved by the animal care committee of the Minister of Public Health, and in accordance with guidelines from the European Union and NIH guide for care and use of laboratory animals. In all experiments, control mice were (Skinner, 1997) wild-type mice and single transgenic, expressing only the activator tTA protein or carrying the responder transgene, because these did not show any difference in all the behavioral and morphological analyses performed.…”

Section: Animalsmentioning

confidence: 99%

“…Characteristic neuropathological findings in SCA1 are the loss of Purkinje cells in the cerebellum and neurons in the inferior olivary complex (Robitaille et al, 1995). As described for other polyglutamine diseases such as Huntingdon's disease (HD) Davies et al, 1997), the presence of neuronal intranuclear inclusions (NIs) in Purkinje cells in human patients and in a transgenic mouse model (Skinner et al, 1997) represents a pathological hallmark of SCA 1. Recent evidence shows that compounds that increase inclusion formation might reduce cellular pathology in several neurodegenerative disorders (Bodner et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Giovannoni

Maggio²,

Bianco³

et al. 2007

Neuron Glia Biol.

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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeats within the coding sequence of the ataxin-1 protein. In the present study, we used a conditional transgenic mouse model of SCA1 to investigate very early molecular and morphological changes related to the behavioral phenotype. In mice with neural deficits detected by rotarod performance, and simultaneous spatial impairments in exploratory activity and uncoordinated gait, we observed both significant altered expression and patchy distribution of excitatory amino acids transporter 1. The molecular changes observed in astroglial compartments correlate with changes in synapse morphology; synapses have a dramatic reduction of the synaptic area external to the postsynaptic density. By contrast, Purkinje cells demonstrate preserved structure. In addition, severe reactive astrocytosis matches changes in the glial glutamate transporter and synapse morphology. We propose these morpho-molecular changes are the cause of altered synaptic transmission, which, in turn, determines the onset of the neurological symptoms by altering the synaptic transmission in the cerebellar cortex of transgenic animals. This model might be suitable for testing drugs that target activated glial cells in order to reduce CNS inflammation.Keywords: EAAT1, synaptic plasticity, SCA1, neurodegeneration INTRODUCTIONThe contribution of non-neuronal cells to the pathogenesis of neurodegenerative diseases has been described although the mechanism remains poorly understood. The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al., 2006).Excitatory amino acids transporter 1 (EAAT1, also known as GLAST) is the major glutamate transporter in the cerebellum (Lehre and Danbolt, 1998). It is expressed strongly by astrocytes in the molecular layer of the cerebellum and is at highest density on Bergmann glia. EAAT1 is not detected in neurons (Ginsberg et al., 1995). EAAT1 present on the plasma membrane of the astrocytic processes and cell bodies (Chaudhry et al., 1995). Targeting of EAAT1 is regulated carefully on astroglial membranes facing the neuropil, large dendrites, cell bodies and capillary endothelium (Danbolt, 2001). Therefore, its distribution follows the morphological changes of astrocytes during inflammatory processes. Recently, in a mouse model of reactive astrocytosis in the spinal cord, it has been reported that this glial process includes a marked proteolytic cascade having as substrates glial transporters. Subsequent changes in neurotransmitter uptake represent the basis of morphological and functional changes that sustain central plasticity . Moreover, glial activation involves changes in cell phenotype and gene expression that might trig...

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“…The blots were incubated with anti-ataxin 11NQ polyclonal antibody (1:5000 dilution) [17] and anti-polyQ 1C2 MoAb (1:6000 dilution) [20], followed by a horseradish peroxidase (HRP) labeled second antibody (1:1000 dilution). Immunodetection was carried out with the enhanced chemiluminescence Western blot system (Amersham Pharmacia).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Despite the wide expression pattern of ataxin-1, a selective degeneration of cerebellar Purkinje cells and brainstem neurons can be found in SCA1. The analyses of the subcellular localization of ataxin-1 in the Purkinje cells of SCA1 transgenic mice, neurons of SCA1 patients, and in transfected COS-1 cells, have revealed that normal ataxin-1 localizes to several nuclear structures and that it associates with the nuclear matrix, whereas the expanded ataxin-1 localizes in a few large structures, in the affected neurons [17].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Calabresi

Guida

Servadio³

et al. 2001

Brain Research Bulletin

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Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expandedinterrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with selfaggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation. © 2001 Elsevier Science Inc.KEY WORDS: Spinocerebellar ataxia type 1, SCA1, Trinucleotide expansion, Amyloid-like protein aggregates.

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Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures

Cited by 512 publications

References 26 publications

Regulation of microRNA expression by HMGA1 proteins

Regulation of microRNA expression by HMGA1 proteins

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

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