A SCA7 CAG/CTG repeat expansion is stable in Drosophila melanogaster despite modulation of genomic context and gene dosage

Jackson, Sara L.; Whitworth, Alexander J.; Greene, Jennifer C.; Libby, Randell T.; Baccam, Sandy L.; Pallanck, Leo J.; Spada, Albert R. La

doi:10.1016/j.gene.2004.12.008

Cited by 23 publications

(13 citation statements)

References 38 publications

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“…Our results clearly demonstrate that somatic repeat instability is not required for the onset of progressive motor deficits and selective neuropathology in the BACHD model. Our study is consistent with previous studies from other polyQ disease mouse models (i.e., SCA1 and SCA7 mice) suggesting somatic repeat instability in a given region is not correlated with neuropathology (Orr et al, 1993;Libby et al, 2003;Watase and Zoghbi, 2003;Jackson et al, 2005). Although our model argues against the role of somatic instability in selective neuropathogenesis in HD, our data could not exclude the possibility that somatic repeat expansion could be a modifier of disease pathogenesis in vivo.…”

Section: Discussionsupporting

confidence: 88%

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

Gray¹,

Shirasaki²,

Cepeda³

et al. 2008

Journal of Neuroscience

566

696

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To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.

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Section: Discussionsupporting

confidence: 88%

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

Gray¹,

Shirasaki²,

Cepeda³

et al. 2008

Journal of Neuroscience

566

696

View full text Add to dashboard Cite

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“…We have now used these transgenes to generate SCA7 Drosophila. Another SCA7 fly was generated previously using full-length ATXN7 with 90Q (Jackson et al, 2005), but no obvious phenotype was observed (Albert R. La Spada, personal communication). Interestingly, previous studies described an abundant N-terminal cleavage fragment of expanded ATXN7 in mouse models of SCA7 Garden et al, 2002) and in fibroblasts of a juvenile-onset SCA7 patient (Garden et al, 2002).…”

Section: Human Atxn7t Is Expressed and Processed Normally In Transgenmentioning

confidence: 99%

A Conditional Pan-NeuronalDrosophilaModel of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes

Latouche¹,

Lasbleiz²,

Martin³

et al. 2007

J. Neurosci.

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Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin 7 (ATXN7) protein, a member of a multiprotein complex involved in histone acetylation. We have created a conditional Drosophila model of SCA7 in which expression of truncated ATXN7 (ATXN7T) with a pathogenic polyQ expansion is induced in neurons in adult flies. In this model, mutant ATXN7T accumulated in neuronal intranuclear inclusions containing ubiquitin, the 19S proteasome subunit, and HSP70 (heat shock protein 70), as in patients. Aggregation was accompanied by a decrease in locomotion and lifespan but limited neuronal death. Disaggregation of the inclusions, when expression of expanded ATXN7T was stopped, correlated with improved locomotor function and increased lifespan, suggesting that the pathology may respond to treatment. Lifespan was then used as a quantitative marker in a candidate gene approach to validate the interest of the model and to identify generic modulators of polyQ toxicity and specific modifiers of SCA7. Several molecular pathways identified in this focused screen (proteasome function, unfolded protein stress, caspase-dependent apoptosis, and histone acetylation) were further studied in primary neuronal cultures. Sodium butyrate, a histone deacetylase inhibitor, improved the survival time of the neurons. This model is therefore a powerful tool for studying SCA7 and for the development of potential therapies for polyQ diseases.

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“…Investigations of CAG-repeat expansion in different species such as yeast, mice and Drosophila have come to conflicting conclusions regarding the influence of the Fen1 protein (Freudenreich et al, 1998;Jackson et al, 2005;Spiro and McMurray, 2003;van den Broek et al, 2006). In human patients, no null-mutations were found in the coding region of the Fen1 protein (Otto et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…However, no expansion was seen of a (CTG) n ·(CAG) n repeat in a Myotonic dystrophy type 1 (DM1) knockin model in mice (van den Broek et al, 2006). There appears to be a strong species dependence in triplet expansion, as in Drosophila a SCA7 CAG90 repeat appeared completely stable in a series of strains with mutations of DNA repair genes, among them PCNA, MutS and Fen1 (Jackson et al, 2005). The influence of reduced Fen1 expression has not been investigated in human cells, but a study of Huntingtin patients found no evidence for null-mutations in the protein-coding region of Fen1 (Otto et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Huntingtin triplet-repeat locus is stable under long-term Fen1 knockdown in human cells

Moe

Sörbo

Holen

2008

Journal of Neuroscience Methods

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A SCA7 CAG/CTG repeat expansion is stable in Drosophila melanogaster despite modulation of genomic context and gene dosage

Cited by 23 publications

References 38 publications

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

A Conditional Pan-NeuronalDrosophilaModel of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes

Huntingtin triplet-repeat locus is stable under long-term Fen1 knockdown in human cells

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