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

• DOI: 10.1038/s41398-018-0319-z
• Publication Date: 2018-12-03T15:38:00Z
• Authors: Shan Jiang; Natalie Wen; Zeran Li; Umber Dube; Jorge Del Aguila; John Budde; Rita Martinez; Simon Hsu; Maria V. Fernandez; Nigel J. Cairns; ; ; Oscar Harari; Carlos Cruchaga; Celeste M. Karch
• Keywords: Tauopathy; Frontotemporal lobar degeneration; Tau protein

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