Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice

Garden, Gwenn A.; Libby, Randell T.; Fu, Ying Hui; Kinoshita, Yoshito; Huang, Jing; Possin, Daniel E.; Smith, Anthony; Martinez, Refugio A.; Fine, Gerald; Grote, Sara K.; Ware, Carol B.; Einum, David D.; Morrison, Richard S.; Ptáček, Louis J.; Sopher, Bryce L.; Spada, Albert R. La

doi:10.1523/jneurosci.22-12-04897.2002

Cited by 146 publications

(148 citation statements)

References 38 publications

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“…Quantification of immunostaining results indicated that NIs formed in 20.6% of cells expressing the mutant ATXN7 protein (n = 725 cells counted, SEM ± 1.7%), but were absent in those expressing its WT counterpart (n = 676 cells counted). To further highlight the similarities between our SCA7 astrocyte model and previously reported SCA7 patient and laboratory model data (4,5,19), we observed an apparent polyQdependent increase in ATXN7 protein stability (Fig. 1B).…”

Section: Resultssupporting

confidence: 83%

“…Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2,6,7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2,4). Of these, the model used by Custer et al (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms.…”

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confidence: 99%

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Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.chromatin | SAGA complex | histone modification A s a member of the polyglutamine expansion disorder family, Spinocerebellar ataxia type 7 (SCA7) is an autosomaldominant hereditary disease characterized by cerebellar and retinal degeneration eventually leading to death (1). Although the ataxin-7 (ATXN7) protein is expressed throughout the body, pathology is localized primarily within the cerebellum and retina. Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2, 6, 7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2, 4). Of these, the model used by Custer et al. (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms. Astrocytes play a crucial role in the regulation of synaptic formation and function by ensheathing axon-dendrite connections to form a structure known as the tripartite synapse (9). This intimate interaction allows astrocytes to modulate synaptic function through the release of chemical messengers and the regulation of neurotransmitter and ion concentration within the synapse (9-11). The identification of tissue specificity factors and characterization of associated molecular mechanisms involved in their deregulation will facilitate a more comprehensive understanding of disease-associated events and advance efforts to develop effective treatments.The ATXN7 protein is an integral subunit of GCN5 (general control of amino acid synthesis-5; KAT2A)...

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Section: Resultssupporting

confidence: 83%

mentioning

confidence: 99%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Proteolytic processing of ATXN7, believed to occur in the nucleus, has been observed in SCA7 and is thought to generate smaller more toxic polyQ fragments (Garden et al, 2002;Young et al, 2007;Yu et al, 2012;Yvert et al, 2001). We have previously shown that in the stable PC12 cell model used in this study, full-length ATXN7 is mainly found in the nucleus, whereas ATXN7 fragments localize and aggregate both in the nucleus and the cytoplasm .…”

Section: Discussionmentioning

confidence: 63%

Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

Muñoz-Alarcón

Ajayi

et al. 2013

J Mol Neurosci

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However, recently evidence implicating autophagic dysfunction in these disorders has also been reported. In this study we show that the SCA7 polyglutamine protein ataxin-7 (ATXN7) reduces the autophagic activity via a previously unreported mechanism involving p53-mediated disruption of two key proteins involved in autophagy initiation. We show that in mutant ATXN7 cells, an increased p53-FIP200 interaction and co-aggregation of p53-FIP200 into ATXN7 aggregates result in decreased soluble FIP200 levels and subsequent destabilization of ULK1. Together, this leads to a decreased capacity for autophagy induction via the ULK1-FIP200-Atg13-Atg101 complex. We also show that treatment with a p53 inhibitor, or a blocker of ATXN7 aggregation, can restore the soluble levels of FIP200 and ULK1, as well as increase the autophagic activity and reduce ATXN7 toxicity. Understanding the mechanism behind polyQ-mediated inhibition of autophagy is of importance if therapeutic approaches based on autophagy stimulation should be developed for these disorders.

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“…Even more remarkably, we show that Igfbp5 down-regulation takes place through a non-cell-autonomous mechanism. Previous work supporting the importance of intercellular interactions in polyglutamine disorders has relied on the use of a truncated fragment of huntingtin or the overexpression of the mutant ATXN7 protein in cells that provide support to PCs (25)(26)(27). To date, however, this issue has not been investigated in KI models, whereby the mutant protein is expressed in the endogenous manner such that intercellular interactions and their influence on selective vulnerability can be investigated in the endogenous disease context.…”

Section: Discussion Common Transcriptional Changes Occur In Early-symmentioning

confidence: 99%

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Gatchel¹,

Watase

Thaller³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cellautonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.cerebellum ͉ neurodegeneration ͉ polyglutamine ͉ Purkinje cell ͉ granule neuron P olyglutamine diseases are a group of inherited neurodegenerative disorders that include spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). They are caused by expansion of CAG repeats encoding a polyglutamine tract in different proteins (1). Evidence suggests that the polyglutamine expansion confers toxicity predominantly through a gain-of-function mechanism, although loss of function may also play a role (1, 2). Despite widespread expression of the disease proteins in the central nervous system (CNS), there is selective vulnerability of specific neurons in each disease (1). Such selective neuronal vulnerability gives rise to the specific features of each disease.SCA1 and SCA7 have distinct features while also sharing some key similarities. In SCA1, primary symptoms include ataxia, dysarthria, and bulbar dysfunction, whereas cognitive impairment is more varied (1). This presentation is associated with cerebellar atrophy and loss of Purkinje cells (PCs) and secondary loss of granule neurons (1). In SCA7, progressive visual loss, cerebellar ataxia, and dysarthria are the most common clinical features (3). In addition to retinal degeneration, cerebellar PCs and neurons of the dentate nucleus and inferior olive are among the earliest to degenerate (3).Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation (4-8), and transcriptional defects can be detected in e...

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Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice

Cited by 146 publications

References 38 publications

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

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