dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1.

dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. Research Abstract Details 

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dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. Abstract Text:

Ismael Al-Ramahi,Alma M ,Janghoo Lim,Minghang Zhang,Rie Sorensen,Maria de Haro,Joana Branco,Stefan M Pulst,Huda Y Zoghbi,Juan Botas,

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders sharing atrophy of the cerebellum as a common feature. SCA1 and SCA2 are two ataxias caused by expansion of polyglutamine tracts in Ataxin-1 (ATXN1) and Ataxin-2 (ATXN2), respectively, two proteins that are otherwise unrelated. Here, we use a Drosophila model of SCA1 to unveil molecular mechanisms linking Ataxin-1 with Ataxin-2 during SCA1 pathogenesis. We show that wild-type Drosophila Ataxin-2 (dAtx2) is a major genetic modifier of human expanded Ataxin-1 (Ataxin-1[82Q]) toxicity. Increased dAtx2 levels enhance, and more importantly, decreased dAtx2 levels suppress Ataxin-1[82Q]-induced neurodegeneration, thereby ruling out a pathogenic mechanism by depletion of dAtx2. Although Ataxin-2 is normally cytoplasmic and Ataxin-1 nuclear, we show that both dAtx2 and hAtaxin-2 physically interact with Ataxin-1. Furthermore, we show that expanded Ataxin-1 induces intranuclear accumulation of dAtx2/hAtaxin-2 in both Drosophila and SCA1 postmortem neurons. These observations suggest that nuclear accumulation of Ataxin-2 contributes to expanded Ataxin-1-induced toxicity. We tested this hypothesis engineering dAtx2 transgenes with nuclear localization signal (NLS) and nuclear export signal (NES). We find that NLS-dAtx2, but not NES-dAtx2, mimics the neurodegenerative phenotypes caused by Ataxin-1[82Q], including repression of the proneural factor Senseless. Altogether, these findings reveal a previously unknown functional link between neurodegenerative disorders with common clinical features but different etiology.

dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. Publishing Authors By Initials

I Al-Ramahi,AM ,J Lim,M Zhang,R Sorensen,M de Haro,J Branco,SM Pulst,HY Zoghbi,J Botas,

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dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: PLoS genetics

VOLUME: 3

Page Numbers: e234

Journal Abbreviation: PLoS Genet.

ISSN: 1553-7404

DAY: 16

MONTH: 11

YEAR: 2007

dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. Information

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LANGUAGE: eng

NlmUniqueID: 101239074

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Grant and Affiliation Information for dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1.

AFFILIATION: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

Country: United States

AGENCY: United States NINDS

GRANT: NS42179

ACRONYM: NS

MEDLINETA: PLoS Genet

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ACCESSION NUMBER: NP_732034

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