Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Abstract

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P < 1 × 10−3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants

“…Pick's disease (PiD) is the most common FTLD-tau subtype underlying bvFTD, but its severe neuronal loss makes it difficult to study early neuronal targets of tau aggregation. Given the growing efforts to model FTLD tauopathy using cell models derived from patients with FTLD-tau/MAPT [13][14][15], we reasoned that an assessment of VEN and fork cell vulnerability in this patient group could provide an important backdrop for the field. We hypothesized that ACC and FI VENs and fork cells are prone to tau aggregation in FTLD-tau, as they are to TDP-43 aggregation in FTLD-TDP.…”

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

“…Since both genetic and environmental risk factors contribute to the development of neurodegenerative diseases 23,24 , a highly relevant model for testing the neurotoxic effects of heavy metals is the use of iPSC-differentiated neurons carrying PSP-associated mutations. Therefore, we used an iPSC line (F11362.1) generated from an individual carrying a heterozygous mutation in the MAPT gene (R406W) 10 , which has been implicated in PSP and other tauopathies 8,9,25 . Since one of the limitations of using of patient-derived iPSCs is the lack of genetically paired controls, we used the CRISPR/Cas9 genome editing technology 10,26 to generate an isogenic control iPSC line (Fig.…”

“…Therefore, we used an iPSC line (F11362.1) generated from an individual carrying a heterozygous mutation in the MAPT gene (R406W) 10 , which has been implicated in PSP and other tauopathies 8,9,25 . Since one of the limitations of using of patient-derived iPSCs is the lack of genetically paired controls, we used the CRISPR/Cas9 genome editing technology 10,26 to generate an isogenic control iPSC line (Fig. 1a).…”

“…The iPSC line (F11362.1) was generated from epithelial fibroblasts from a heterozygous R406W tau mutation carrier. The skin biopsy was performed after obtaining the donor's written informed consent 10 . The informed consent and the protocol of our study was approved by the Washington University School of Medicine Institutional Review Board and Ethics Committee (2020) 10:569 | https://doi.org/10.1038/s41598-019-56930-w www.nature.com/scientificreports www.nature.com/scientificreports/ (IRB 201104178 and 201306108).…”

“…The mechanisms underlying tau pathology and neuronal death in PSP are largely unknown. Although mutations in several genes, including MAPT (the gene encoding the tau protein) have been associated with PSP, most cases of the disease have no present genetic variations and/or mutations [6][7][8][9][10] . It has also been reported that the exposure to environmental toxins increases the risk of sporadic PSP [11][12][13][14] .…”