Mice Lacking Ataxin-1 Display Learning Deficits and Decreased Hippocampal Paired-Pulse Facilitation

Matilla, Antoni; Roberson, Erik D.; Banfi, Sandro; Morales, Joanella; Armstrong, Dawna L.; Burright, Eric N.; Orr, Harry T.; Sweatt, J. David; Zoghbi, Huda Y.; Matzuk, Martin M.

doi:10.1523/jneurosci.18-14-05508.1998

Cited by 195 publications

(121 citation statements)

References 35 publications

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“…It could be due to the near complete absence of ATXN1 in transduced cells, although we think this is not likely due the fact that chronic, 100% loss of Atxn1 in mice causes transcriptional misregulation but no noted neuropathology or ataxia. 27,28 A second possibility is that the high level expression of miS1 somehow causes toxicity due to abnormal processing of endogenous miRNAs. This can be evaluated in future work to examine endogenous miRNA processing and miRNA activity.…”

Section: Discussionmentioning

confidence: 99%

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Keiser

Monteys

Corbau

et al. 2016

Annals of Neurology

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Objective Spinocerebellar ataxia type 1 is an autosomal dominant fatal neurodegenerative disease caused by a polyglutamine expansion in the coding region of ATXN1. We showed previously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally-expressed RNAi triggers, could prevent disease symptoms in a transgenic mouse model and a knock in mouse model of the disease, using a single dose of virus. Here, we set out to test if RNAi triggers targeting ATXN1 could not only prevent, but also reverse disease readouts when delivered after symptom onset. Methods We administered recombinant adeno-associated virus (rAAV) expressing miS1, an artificial miRNA targeting human ATXN1 mRNA (rAAV.miS1) to a mouse model of SCA1 (B05 mice). Viruses were delivered prior to or after symptom onset at multiple doses. Control B05 mice were treated with rAAVs expressing a control artificial miRNA, or with saline. Animal behavior, molecular phenotypes, neuropathology and magnetic resonance spectroscopy were done on all groups and data were compared to wildtype littermates. Results We found that SCA1 phenotypes could be reversed by partial suppression of human mutant ATXN1 mRNA by rAAV.miS1 when delivered after symptom onset. We also identified the therapeutic range of rAAV.miS1 that could prevent or reverse disease readouts. Interpretation SCA1 disease may be reversible by RNAi therapy, and the doses required for advancing this therapy to humans are delineated.

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Section: Discussionmentioning

confidence: 99%

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Keiser

Monteys

Corbau

et al. 2016

Annals of Neurology

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“…The nucleotide sequence (s) The normal function of ATXN1 is still unclear. ATXN1 KO mice display impairments in learning and memory (4). ATXN1 also stimulates ␤-secretase processing of ␤-amyloid precursor protein (11).…”

Section: * This Work Was Supported By the Canadian Institutes For Heamentioning

confidence: 99%

“…First, loss of function of ATXN1 is not the primary cause of toxicity in SCA1 as mice lacking ATXN1 do not show a SCA1-like phenotype (4). Yet loss of function may partially contribute to neuronal dysfunction through transcriptional dysregulation and abnormal protein interactions (5)(6)(7).…”

mentioning

confidence: 99%

An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein

Bergeron

Lapointe

Bissonnette

et al. 2013

Journal of Biological Chemistry

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Background:The spinocerebellar ataxia type 1 (SCA1) gene encoding ataxin-1 (ATXN1) contains an alternative open reading frame overlapping the ATXN1 coding sequence. Results: The alternative ATXN1 protein is constitutively co-expressed and interacts with ATXN1 N terminus. Alternative ATXN1 is also an RNA binding protein. Conclusion:ATXN1 is a genuine dual coding gene. Significance: Alternative ATXN1 may regulate the function of ATXN1 in physiological and pathological conditions.

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“…the phenotype requires the expression of mutant ATXN1 with an expanded repeat tract (13), whereas loss of function of ATXN1 does not cause an SCA1-like phenotype in mice (14). Data revealing that the toxic effects of the disease causing polyglutamine expansion are determined by the context of other domains in the ATXN1 protein suggested that the endogenous normal function and regulation of ATXN1 interactions are critical for pathogenesis.…”

Section: Atxn1 Protein: Function and Relationship To Disease Pathogenmentioning

confidence: 99%

Pathogenic Mechanisms of a Polyglutamine-mediated Neurodegenerative Disease, Spinocerebellar Ataxia Type 1

Zoghbi

Orr

2009

Journal of Biological Chemistry

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Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative diseases caused by the expansion of a CAG trinucleotide repeat encoding a polyglutamine tract. SCA1 patients lose motor coordination and develop slurred speech, spasticity, and cognitive impairments. Difficulty with coordinating swallowing and breathing eventually causes death. Genetic evidence indicates that the disease mutation induces a toxic gain of function in the SCA1 encoded protein ATXN1. The discovery that residues in ATXN1 outside of the polyglutamine tract are crucial for pathogenesis hinted that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at Ser 776 and a subsequent alteration in its interaction with other cellular proteins. Moreover, the finding that other ATXN1 interactions are decreased in disease suggests that the polyglutamine expansion contributes to disease by both a gain-of-function mechanism and partial loss of function.

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Mice Lacking Ataxin-1 Display Learning Deficits and Decreased Hippocampal Paired-Pulse Facilitation

Cited by 195 publications

References 35 publications

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein

Pathogenic Mechanisms of a Polyglutamine-mediated Neurodegenerative Disease, Spinocerebellar Ataxia Type 1

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