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.

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

“…This trend is evident in both wild‐type mice during physiological aging and in a premature aging mouse model, suggesting that alternative splicing might be more important in the aging process than has previously been noted. Our results are in agreement with those of other recent studies that have shown an effect of age on AS in human brain (Tollervey et al ., 2011; Mazin et al ., 2013), human peripheral blood leukocytes (Harries et al ., 2011), and senescent fibroblasts induced by telomere shortening (Cao et al ., 2011). To our knowledge, this is the first study to show that the amount of age‐related AS increases with more advanced age (4–18 months compared to 4–28 months) and in several tissues.…”

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

“…In this report the ER␤-HnRNP H interaction was enhanced by E2 in young animals but was decreased or unchanged by E2 in aged animals, suggesting that in aged animals the influence of E2 over the actions of an ER␤-HnRNP H complex might be altered. Estrogen receptors have been shown to participate on some level in miRNA processing (68,69) and mRNA splicing (13), and evidence suggests that aging may lead to a global increase in alternative splicing (70). Recent findings demonstrate that ER␤ is differentially spliced depending upon age and E2 treatment (71).…”

Proper splicing contributes to visual function in the aging Drosophila eye

“…Recent studies show that changes in splicing are part of the transcriptional signature of aging cells (Deschênes & Chabot, 2017; Stegeman & Weake, 2017). Age‐associated changes in alternative splicing have been observed in human brain and in mouse skin, skeletal muscle, bone, thymus, and white adipose tissue (Rodríguez et al, 2016; Tollervey et al, 2011). Splicing is a highly regulated and integral part of proper gene expression; thus, slight perturbations in splicing can lead to altered function and/or expression.…”

“…Many splicing factors show age‐related changes in their expression that correlate with changes in alternative splicing during aging (Harries et al, 2011; Lee et al, 2016; Mazin et al, 2013; Rodríguez et al, 2016; Tollervey et al, 2011; Wood, Craig, Li, Merry, & Magalhães, 2013). For example, as many as one‐third of all splicing factors exhibit altered expression with age in human blood (Holly et al, 2013).…”