title: Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains.
abstract: TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model.In total 68 missense variants were identified of which 19 (MAF < 1%) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P = 0.0349, RR = 1.46 [95% CI 1.03-2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1 + 5G > C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis.Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. jonathan.janssens@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. jonathan.janssens@molgen.vib-ua.be.|Translational Neurobiology Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. jonathan.janssens@molgen.vib-ua.be.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janssens
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. Stephanie.Philtjens@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Stephanie.Philtjens@molgen.vib-ua.be.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Philtjens
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. Gernot.Kleinberger@mail03.med.uni-muenchen.de.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Gernot.Kleinberger@mail03.med.uni-muenchen.de.|Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany. Gernot.Kleinberger@mail03.med.uni-muenchen.de.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Gernot.Kleinberger@mail03.med.uni-muenchen.de.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. Sara.VanMossevelde@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Sara.VanMossevelde@molgen.vib-ua.be.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Mossevelde
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. julie.vanderzee@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. julie.vanderzee@molgen.vib-ua.be.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. rita.cacace@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. rita.cacace@molgen.vib-ua.be.
authors.forename: Rita
authors.initials: R
authors.lastname: Cacace
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. sebastiaan.engelborghs@uantwerpen.be.|Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium. sebastiaan.engelborghs@uantwerpen.be.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. annesieben@yahoo.com.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. annesieben@yahoo.com.|Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium. annesieben@yahoo.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Sieben
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. julia.banzhaf@dzne.lmu.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Banzhaf-Strathmann
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. lubina.dillen@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. lubina.dillen@molgen.vib-ua.be.
authors.forename: Lubina
authors.initials: L
authors.lastname: Dillen
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. celine.merlin@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. celine.merlin@molgen.vib-ua.be.
authors.forename: Céline
authors.initials: C
authors.lastname: Merlin
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. ivy.cuijt@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. ivy.cuijt@molgen.vib-ua.be.
authors.forename: Ivy
authors.initials: I
authors.lastname: Cuijt
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. caroline.robberecht@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. caroline.robberecht@molgen.vib-ua.be.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robberecht
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. bettina.schmid@med.uni-muenchen.de.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. bettina.schmid@med.uni-muenchen.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schmid
authors.affiliation: Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium. Patrick.Santens@UGent.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.affiliation: Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium. adrian.ivanoiu@uclouvain.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivanoiu
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium. mathieu.vandenbulcke@uz.kuleuven.ac.be.|Department of Old Age Psychiatry and Memory Clinic, University of Leuven, Leuven, Belgium. mathieu.vandenbulcke@uz.kuleuven.ac.be.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vandenbulcke
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium. rik.vandenberghe@uz.kuleuven.ac.be.|Department of Neurology, University Hospitals Leuven, Leuven, Belgium. rik.vandenberghe@uz.kuleuven.ac.be.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. patrick.cras@uantwerpen.be.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium. patrick.cras@uantwerpen.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. p.p.de.deyn@umcg.nl.|Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium. p.p.de.deyn@umcg.nl.|Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. p.p.de.deyn@umcg.nl.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. jean-jacques.martin@uantwerpen.be.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Stuart.Maudsley@molgen.vib-ua.be.|Translational Neurobiology Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. Stuart.Maudsley@molgen.vib-ua.be.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. chaass@med.uni-muenchen.de.|Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany. chaass@med.uni-muenchen.de.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. chaass@med.uni-muenchen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. marc.cruts@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. marc.cruts@molgen.vib-ua.be.
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.affiliation: Neurodegenerative Brain Diseases group, VIB Department of Molecular Genetics, University of Antwerp - CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001530:Belgium; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D064448:Filamins / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D000077153:Progranulins; D034622:RNA Interference / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D064448:Filamins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins