Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

Abstract

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here we integrated transcriptomic and epigenomic analyses of postmortem human brains of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways between patient groups. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Small RNA-seq data and verification experiments in cellular models identified up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. These findings shed light on novel mechanistic and pathophysiological hallmarks of FTD. The data represent the 1st phase of a multi-omics, multi-model data resource for FTD research which allows in-depth molecular research into disease mechanisms that will further mechanistic FTD research.

Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

“…In all brain regions, we also detected strong enrichment for extracellular matrix (ECM) remodelling, a cellular process that is poorly understood in FTLD. One of the few lines of evidence supporting ECM dysregulation in FTLD comes from a transcriptomic study done on individual genetic subgroups -C9orf72, GRN, and MAPT (Menden et al 2021). In all three groups, Menden et al detected increased expression of key ECM genes, including matrix metalloproteinases (MMPs).…”

“…CHCHD10 encodes a mitochondrial protein, and missense mutations in this gene have been observed in familial FTD cases and associated with impaired oxidative phosphorylation (Bannwarth et al 2014). DCTN1, which encodes a motor protein involved in vesicular transport, has been shown to be downregulated in FTD and ALS (Menden et al 2021;Kuźma-Kozakiewicz et al 2013). GFAP is a marker of astrocytes previously reported to be upregulated in FTD (Hallmann et al 2017), and the ADAMTS2 gene encodes an enzyme responsible for collagen production (Hurskainen et al 1999).…”

Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD

“…The differentiation protocol was performed as described (Dhingra et al, 2020). In short, smNPC stable inducible line for NGN2 expression was generated using a single lentivirus vector system consisting of pLV_TRET_hNgn2_UBC_BSD_T2A_rtTA3 (Menden et al, 2021). Stable NGN2 smNPCs were used within 8 passages post-transduction.…”

iPS Cell-Based Model for MAPT Haplotype as a Risk Factor for Human Tauopathies Identifies No Major Differences in TAU Expression

“…For rapid differentiation of smNPCs into neurons, the inducible lentivirus expression construct for the human transcription factor NEUROGENIN-2 (pLV_TRET_hNgn2_UBC_Blast_T2A_rtTA3) was introduced into the smNPCs ( Menden et al, 2021 ). The vector contains NGN2 under control of the tetracycline operator and a blasticidin resistance.…”