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A yeast functional screen predicts new candidate ALS disease genes
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2011 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 52, 20881-20890 p.Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Place, publisher, year, edition, pages
2011. Vol. 108, no 52, 20881-20890 p.
Keyword [en]
amyotrophic-lateral-sclerosis; frontotemporal lobar degeneration; drosophila model; fus mutations; tdp-43 proteinopathy; amyloid pores; wild-type; toxicity; neurodegeneration; aggregation
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Neurosciences
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URN: urn:nbn:se:umu:diva-51465DOI: 10.1073/pnas.1109434108ISI: 000298479900012OAI: oai:DiVA.org:umu-51465DiVA: diva2:482668
Available from: 2012-01-24 Created: 2012-01-23 Last updated: 2017-12-08Bibliographically approved

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Ingre, CarolineAndersen, Peter M

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