RT Journal
A1 Tollervey, James R.
A1 Wang, Zhen
A1 Hortobágyi, Tibor
A1 Witten, Joshua T.
A1 Zarnack, Kathi
A1 Kayikci, Melis
A1 Clark, Tyson A.
A1 Schweitzer, Anthony C.
A1 Rot, Gregor
A1 Curk, Tomaž
A1 Zupan, Blaž
A1 Rogelj, Boris
A1 Shaw, Christopher E.
A1 Ule, Jernej
T1 Analysis of alternative splicing associated with aging and neurodegeneration in the human brain
JF Genome Research 
JO Genome Research 
YR 2011 
FD October 01 
VO 21 
IS 10 
SP 1572 
OP 1582 
DO 10.1101/gr.122226.111 
UL http://genome.cshlp.org/content/21/10/1572.abstract 
AB 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.