Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations

Cyril Pottier, Ligia Mateiu, Matthew C. Baker, Mariely Dejesus-Hernandez, Cristina Teixeira Vicente, Nicole A. Finch, Shulan Tian, Marka Van Blitterswijk, Melissa E. Murray, Yingxue Ren, Leonard Petrucelli, Björn Oskarsson, Joanna M. Biernacka, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, Keith A. Josephs, Yan W. Asmann, Dennis W. Dickson, Rosa Rademakers

Research output: Contribution to journalArticlepeer-review

Abstract

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Original languageEnglish (US)
Pages (from-to)2472-2485
Number of pages14
JournalBrain
Volume145
Issue number7
DOIs
StatePublished - Jul 1 2022

Keywords

  • GABA
  • GRN mutation
  • deconvolution
  • frontotemporal lobar degeneration
  • transcriptome

ASJC Scopus subject areas

  • Medicine(all)

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