title: Analysis of alternative splicing associated with aging and neurodegeneration in the human brain.
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.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: James R
authors.initials: JR
authors.lastname: Tollervey
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Witten
authors.forename: Kathi
authors.initials: K
authors.lastname: Zarnack
authors.forename: Melis
authors.initials: M
authors.lastname: Kayikci
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Clark
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Schweitzer
authors.forename: Gregor
authors.initials: G
authors.lastname: Rot
authors.forename: Tomaž
authors.initials: T
authors.lastname: Curk
authors.forename: Blaž
authors.initials: B
authors.lastname: Zupan
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics; D015536:Down-Regulation; D005091:Exons; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000090682:Neuro-Oncological Ventral Antigen; D020411:Oligonucleotide Array Sequence Analysis; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D025341:Principal Component Analysis; D020033:Protein Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D013702:Temporal Lobe / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; C490650:CHL1 protein, human; D015815:Cell Adhesion Molecules; D007473:Ion Channels; C491152:NRCAM protein, human; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein