PT  - JOURNAL ARTICLE
AU  - Kevin Menden
AU  - Margherita Francescatto
AU  - Tenzin Nyima
AU  - Cornelis Blauwendraat
AU  - Ashutosh Dhingra
AU  - Melissa Castillo-Lizardo
AU  - Noémia Fernandes
AU  - Lalit Kaurani
AU  - Deborah Kronenberg-Versteeg
AU  - Burcu Atarsu
AU  - Eldem Sadikoglou
AU  - Barbara Borroni
AU  - Salvador Rodriguez-Nieto
AU  - Javier Simon-Sanchez
AU  - Andre Fischer
AU  - David Wesley Craig
AU  - Manuela Neumann
AU  - Stefan Bonn
AU  - Patrizia Rizzu
AU  - Peter Heutink
TI  - Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia
AID  - 10.1101/2020.12.01.405894
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.12.01.405894
4099  - http://biorxiv.org/content/early/2021/03/12/2020.12.01.405894.short
4100  - http://biorxiv.org/content/early/2021/03/12/2020.12.01.405894.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.