Needless to say (but I’m going to anyway), I am pleased as punch that my lab’s most recent offering unto the body of scientific literature (“Analysis of alternative splicing associated with aging and neurodegeneration in the human brain”) was put on the cover of the current issue of Genome Research. In this paper, we investigated the connections between alternative splicing profiles in the aging brain and in brains suffering from neurodegenerative disorders, like Alzheimer’s disease. It is important to note that we were characterizing the alternative splicing differences associated with aging and disease, not identifying splicing changes that cause the diseases or the symptoms. Such questions will require ongoing work, which this study will, hopefully, help guide.
The artwork is by the study’s lead author, James Tollervey, who is creative, talented, and tall, all at the same time. My contribution was to conceive of and execute the data analyses leading to the paper’s first figure.
Analysis of alternative splicing associated with aging and neurodegeneration in the human brain
James R. Tollervey, Zhen Wang, Tibor Hortobágyi, Joshua T. Witten, Kathi Zarnack, Melis Kayikci, Tyson A. Clark, Anthony C. Schweitzer, Gregor Rot, Tomaž Curk, Blaž Zupan, Boris Rogelj, Christopher E. Shaw, and Jernej Ule
Genome Res. October 2011 21: 1572-1582; Published in Advance August 16, 2011, doi:10.1101/gr.122226.111
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.