Analysis of alternative splicing associated with aging and neurodegeneration in the human brain
- James R. Tollervey1,
- Zhen Wang1,
- Tibor Hortobágyi2,
- Joshua T. Witten1,
- Kathi Zarnack3,
- Melis Kayikci1,
- Tyson A. Clark4,
- Anthony C. Schweitzer4,
- Gregor Rot5,
- Tomaž Curk5,
- Blaž Zupan5,
- Boris Rogelj2,
- Christopher E. Shaw2 and
- Jernej Ule1,6
- 1MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom;
- 2MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United Kingdom;
- 3EMBL–European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom;
- 4Expression Research, Affymetrix, Inc., Santa Clara, California 95051, USA;
- 5Faculty of Computer and Information Science, University of Ljubljana, Tržaška 25, SI-1000 Ljubljana, Slovenia
Abstract
Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)–dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)–dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration.
Footnotes
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↵6 Corresponding author.
E-mail jule{at}mrc-lmb.cam.ac.uk.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.122226.111.
- Received February 14, 2011.
- Accepted July 5, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press