Fig. 3
Putatively pathogenic brain somatic mutations associated with tau pathology in Alzheimer’s disease (AD). a Gene-list enrichment test of putatively pathogenic somatic mutations using the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database. Genes with putatively pathogenic brain somatic mutations are significantly overrepresented in PI3K-AKT, mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK) pathways related to tau hyperphosphorylation. Vertical bar represents threshold for Benjamini–Hochberg adjusted P value. b Pathogenic scoring and text-mining results of brain somatic mutations found in AD. PIN1 was most frequently mentioned in relevant biomedical literature and ranked 52th according to Phred-scaled CADD (combined annotation‐dependent depletion) score. c Variant allelic frequency (VAFs) of PIN1 c.477C>T (p.Thr152Met) in blood, bulk hippocampal formation (HIF), and each sub-region of the HIF. PIN1 c.477C > T (p.Thr152Met) were observed. The VAF in each sub-regions of the HIF was 0.51–1.62%. d Comparison of protein expression levels of wild-type and mutant PIN1. PIN1 expression was analyzed in Neuro-2a cells expressing wild-type and the mutant 3× FLAG-hPin1. n = 3 for each experiment. e Effect of Pin1 knockdown on hyperphosphorylation of tau. Expression levels of pThr231-tau were observed in scramble and mPin1-shRNA (short hairpin RNA)-transfected HT22 cells. n = 9 for each experiment. f Effect of Pin1 knockdown on the oligomerization of tau. HT22 cells were co-transfected with tau-BiFC and either scramble or mPin1-shRNA. Then, cellular responses of tau-BiFC fluorescence (green) were measured. n = 20 for each experiment. Scale bar, 250 μm. Each bar represents the mean ± SEM and paired T test were used to determine the significance of each experiment in d–f. ***p < 0.001; ****p < 0.0001. Source data is available as a Source Data file
