TY - JOUR
T1 - Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations
AU - Pottier, Cyril
AU - Mateiu, Ligia
AU - Baker, Matthew C.
AU - Dejesus-Hernandez, Mariely
AU - Teixeira Vicente, Cristina
AU - Finch, Nicole A.
AU - Tian, Shulan
AU - Van Blitterswijk, Marka
AU - Murray, Melissa E.
AU - Ren, Yingxue
AU - Petrucelli, Leonard
AU - Oskarsson, Björn
AU - Biernacka, Joanna M.
AU - Graff-Radford, Neill R.
AU - Boeve, Bradley F.
AU - Petersen, Ronald C.
AU - Josephs, Keith A.
AU - Asmann, Yan W.
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
KW - GABA
KW - GRN mutation
KW - deconvolution
KW - frontotemporal lobar degeneration
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85135420306&partnerID=8YFLogxK
U2 - 10.1093/brain/awab437
DO - 10.1093/brain/awab437
M3 - Article
C2 - 34918030
AN - SCOPUS:85135420306
SN - 0006-8950
VL - 145
SP - 2472
EP - 2485
JO - Brain
JF - Brain
IS - 7
ER -