Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models.

Abstract

Mutations in the microtubule-associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). Yet, the pathogenic events linked to disease remain poorly understood. This study was aimed at identifying genes and pathways that drive to FTLD-tau. To identify the earliest genes and pathways that are dysregulated in FTLD-tau, we detected differentially expressed genes in RNA-seq data generated from induced pluripotent stem cell (iPSC)-derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and 26 brain tissue samples (3 R406W carriers, 7 IVS10+16, 3 P301L, and 13 unrelated controls). We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes. We identified 61 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT R406W carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT R406W carriers. We identified 15 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT IVS10+16 carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT IVS10+16 carriers. We identified 37 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT P301L carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT P301L carriers. Interestingly, there is little overlap among genes differentially expressed for MAPT R406W, MAPT P301L, and MAPT IVS10+16, which suggests that these mutations may lead to tau aggregation and neurodegeneration by different mechanisms. The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to model disease.