Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 52, Pages 20881-20890Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1109434108
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Funding
- National Institutes of Health [1DP2OD004417, 1DP2OD002177-01, 1R01NS065317, 5R21NS067354-02, AG17586, AG10124, P01-AG-09215, NS056070, NS072561, T32-AG00255, R01 AG26251-03A1, R01 NS065782, P50 AG16574]
- University of Pennsylvania Institute on Aging and Alzheimer's Disease Core Center [AG10124]
- ALS Association
- Packard Center for ALS Research at Johns Hopkins
- Ellison Medical Foundation
- Pew Charitable Trusts
- Rita Allen Foundation
- National Institute on Aging [U24 AG21886]
- National Health and Medical Research Council of Australia [1004670, 511941]
- Motor Neurone Disease Research Institute of Australia
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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.
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