TY - JOUR
T1 - Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains
AU - Belgian Neurology BELNEU
AU - Janssens, Jonathan
AU - Philtjens, Stephanie
AU - Kleinberger, Gernot
AU - Van Mossevelde, Sara
AU - van der Zee, Julie
AU - Cacace, Rita
AU - Engelborghs, Sebastiaan
AU - Sieben, Anne
AU - Banzhaf-Strathmann, Julia
AU - Dillen, Lubina
AU - Merlin, Celine
AU - Cuijt, Ivy
AU - Robberecht, Caroline
AU - Schmid, Bettina
AU - Santens, Patrick
AU - Ivanoiu, Adrian
AU - Vandenbulcke, Mathieu
AU - Vandenberghe, Rik
AU - Cras, Patrick
AU - De Deyn, Peter P.
AU - Martin, Jean-Jacques
AU - Maudsley, Stuart
AU - Haass, Christian
AU - Cruts, Marc
AU - Van Broeckhoven, Christine
PY - 2015/11/10
Y1 - 2015/11/10
N2 - 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.
AB - 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.
KW - Filamin C
KW - Genetics
KW - Frontotemporal lobar degeneration
KW - Granulin GRN
KW - Haploinsufficiency
KW - Proteomics
KW - AMYOTROPHIC-LATERAL-SCLEROSIS
KW - LOBAR DEGENERATION
KW - BINDING PROTEIN
KW - HYPERTROPHIC CARDIOMYOPATHY
KW - ALZHEIMERS-DISEASE
KW - VASCULAR DEMENTIA
KW - MUTATIONS
KW - MYOPATHY
KW - IDENTIFICATION
KW - NEUROGRANIN
U2 - 10.1186/s40478-015-0246-7
DO - 10.1186/s40478-015-0246-7
M3 - Article
SN - 2051-5960
VL - 3
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
M1 - 68
ER -