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Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains.

Janssens J, Philtjens S, Kleinberger G, Van Mossevelde S, van der Zee J, Cacace R, Engelborghs S, Sieben A, Banzhaf-Strathmann J, Dillen L, Merlin C, Cuijt I, Robberecht C, Schmid B, Santens P, Ivanoiu A, Vandenbulcke M, Vandenberghe R, Cras P, De Deyn PP, Martin JJ, Maudsley S, Haass C, Cruts M, Van Broeckhoven C, Belgian Neurology (BELNEU) consorti - Acta Neuropathol Commun (2015)

Bottom Line: 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]).The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

FLNC variants identified in patients of the Belgian FTD cohort. a Schematic representation of the short and long isoform of FLNC, which differ from each other in the presence or absence of one exon (marked in red). b 19 FLNC variants identified in patients of the Belgian FTD cohort (marked in red) mapped on the domain structures of the FLNC gene. Represented variants were absent from 920 control individuals. Immunoglobulin (Ig)-like domains are numbered from 1 to 24. CH1 and CH2: calponin homology domains. Assignment of FLNC variants to the corresponding domain structure was based on the UniProt database (http://www.uniprot.org/)
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Fig1: FLNC variants identified in patients of the Belgian FTD cohort. a Schematic representation of the short and long isoform of FLNC, which differ from each other in the presence or absence of one exon (marked in red). b 19 FLNC variants identified in patients of the Belgian FTD cohort (marked in red) mapped on the domain structures of the FLNC gene. Represented variants were absent from 920 control individuals. Immunoglobulin (Ig)-like domains are numbered from 1 to 24. CH1 and CH2: calponin homology domains. Assignment of FLNC variants to the corresponding domain structure was based on the UniProt database (http://www.uniprot.org/)

Mentions: The high prevalence of TDP-43 pathology in FTD and ALS patients suggests that pathways disrupting TDP-43 integrity might be shared between patients with different clinical, pathological and genetic etiologies. In line with the molecular genetic findings, multiple pathways related to RNA-processing, protein aggregation and proteostasis are likely contributing to the multifactorial nature of FTD-ALS disorders [9]. Recently, an unexpected requirement of TDP-43 for muscle maintenance, vessel patterning and perfusion was found upon deletion of the TDP-43 homologues in zebrafish [12]. Several muscle-specific proteins were altered on proteomic analysis of this zebrafish model, underscoring the role of TDP-43 in muscle integrity. The most upregulated protein in TDP-43 knockout zebrafish and in the frontal cortex of FTLD-TDP patients, however, was filamin C (FLNC) [12]. Filamins are evolutionary conserved, multidomain actin-binding proteins involved in the organization of the cytoskeleton and plasma membrane stabilization. Besides cross-linking F-actin filaments, filamins scaffold also a wide range of signaling functions through interactions with more than 90 binding partners including intracellular signaling molecules, transmembrane receptors, and ion channels [13, 14]. The vertebrate filamin family consists of filamin A (FLNA), filamin B (FLNB) and filamin C (FLNC) which share ≈ 70 % homology over the entire protein sequence. Structurally, FLNC is a large homodimer of approximately 290-kDa subunits that consists of an N-terminal actin-binding domain (ABD), composed of two calponin homology domains (CH1 and CH2), followed by 24 Immunoglobulin (Ig)-like repeats [15–17]. Two splice variants have been described for FLNC which differ from each other in the presence of exon 31 encoding the hinge region between Ig-like domains 15 and 16 (Fig. 1a). FLNC expression is largely restricted to cardiac and skeletal muscles, although other non-muscular cells, including neuronal cells, express lower but detectable levels of FLNC [18–20]. In line with the expression pattern of FLNC, mutations identified in FLNC have been shown to be the underlying cause of different progressive muscular dystrophies, including distal and myofibrillar myopathy (DM and MFM, respectively), and hypertrophic cardiomyopathy (HCM) [21–23].Fig. 1


Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains.

Janssens J, Philtjens S, Kleinberger G, Van Mossevelde S, van der Zee J, Cacace R, Engelborghs S, Sieben A, Banzhaf-Strathmann J, Dillen L, Merlin C, Cuijt I, Robberecht C, Schmid B, Santens P, Ivanoiu A, Vandenbulcke M, Vandenberghe R, Cras P, De Deyn PP, Martin JJ, Maudsley S, Haass C, Cruts M, Van Broeckhoven C, Belgian Neurology (BELNEU) consorti - Acta Neuropathol Commun (2015)

FLNC variants identified in patients of the Belgian FTD cohort. a Schematic representation of the short and long isoform of FLNC, which differ from each other in the presence or absence of one exon (marked in red). b 19 FLNC variants identified in patients of the Belgian FTD cohort (marked in red) mapped on the domain structures of the FLNC gene. Represented variants were absent from 920 control individuals. Immunoglobulin (Ig)-like domains are numbered from 1 to 24. CH1 and CH2: calponin homology domains. Assignment of FLNC variants to the corresponding domain structure was based on the UniProt database (http://www.uniprot.org/)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4641381&req=5

Fig1: FLNC variants identified in patients of the Belgian FTD cohort. a Schematic representation of the short and long isoform of FLNC, which differ from each other in the presence or absence of one exon (marked in red). b 19 FLNC variants identified in patients of the Belgian FTD cohort (marked in red) mapped on the domain structures of the FLNC gene. Represented variants were absent from 920 control individuals. Immunoglobulin (Ig)-like domains are numbered from 1 to 24. CH1 and CH2: calponin homology domains. Assignment of FLNC variants to the corresponding domain structure was based on the UniProt database (http://www.uniprot.org/)
Mentions: The high prevalence of TDP-43 pathology in FTD and ALS patients suggests that pathways disrupting TDP-43 integrity might be shared between patients with different clinical, pathological and genetic etiologies. In line with the molecular genetic findings, multiple pathways related to RNA-processing, protein aggregation and proteostasis are likely contributing to the multifactorial nature of FTD-ALS disorders [9]. Recently, an unexpected requirement of TDP-43 for muscle maintenance, vessel patterning and perfusion was found upon deletion of the TDP-43 homologues in zebrafish [12]. Several muscle-specific proteins were altered on proteomic analysis of this zebrafish model, underscoring the role of TDP-43 in muscle integrity. The most upregulated protein in TDP-43 knockout zebrafish and in the frontal cortex of FTLD-TDP patients, however, was filamin C (FLNC) [12]. Filamins are evolutionary conserved, multidomain actin-binding proteins involved in the organization of the cytoskeleton and plasma membrane stabilization. Besides cross-linking F-actin filaments, filamins scaffold also a wide range of signaling functions through interactions with more than 90 binding partners including intracellular signaling molecules, transmembrane receptors, and ion channels [13, 14]. The vertebrate filamin family consists of filamin A (FLNA), filamin B (FLNB) and filamin C (FLNC) which share ≈ 70 % homology over the entire protein sequence. Structurally, FLNC is a large homodimer of approximately 290-kDa subunits that consists of an N-terminal actin-binding domain (ABD), composed of two calponin homology domains (CH1 and CH2), followed by 24 Immunoglobulin (Ig)-like repeats [15–17]. Two splice variants have been described for FLNC which differ from each other in the presence of exon 31 encoding the hinge region between Ig-like domains 15 and 16 (Fig. 1a). FLNC expression is largely restricted to cardiac and skeletal muscles, although other non-muscular cells, including neuronal cells, express lower but detectable levels of FLNC [18–20]. In line with the expression pattern of FLNC, mutations identified in FLNC have been shown to be the underlying cause of different progressive muscular dystrophies, including distal and myofibrillar myopathy (DM and MFM, respectively), and hypertrophic cardiomyopathy (HCM) [21–23].Fig. 1

Bottom Line: 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]).The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus