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

Jonathan Janssens,Sara Van Mossevelde,Julie Van Der Zee,Gernot Kleinberger,Julia Banzhaf-Strathmann,Bettina Schmid,Sebastiaan Engelborghs,Stuart Maudsley,Christian Haass,Marc Cruts,Christine Van Broeckhoven,Lubina Dillen,Ivy Cuijt,Patrick Santens,Patrick Cras,Rita Cacace,Céline Merlin,Rik Vandenberghe,Adrian Ivanoiu,Anne Sieben,Mathieu Vandenbulcke,Caroline Robberecht,Stéphanie Philtjens,Jean‐Jacques Martin ,Peter Paul De Deyn

doi:10.1186/s40478-015-0246-7

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0246-7) contains supplementary material, which is available to authorized users.

Highlights

Frontotemporal dementia (FTD) is a progressive presenile dementia with degeneration of the frontal and anterior temporal lobes of the brain [1]
Using the Textrous! individual processing module we found for the FTD-common protein dataset the strongest correlations between the words ‘dendrites’, ‘growth-associated’, ‘cytoskeleton’, ‘polymerization’, and ‘synapses’ and following proteins: growth associated protein 43/neuromodulin (GAP43), glial fibrillary acidic protein (GFAP), brain acid soluble protein 1 (BASP1), neuroplastin (NPTN) and neuronal pentraxin-1 (NPTX1) (Fig. 5a)
We report a significant association between rare variants in filamin C (FLNC) and FTD

Summary

Introduction

Frontotemporal dementia (FTD) is a progressive presenile dementia with degeneration of the frontal and anterior temporal lobes of the brain [1]. The clinical phenotype of FTD patients is heterogeneous and includes cognitive, behavioral and language impairments with a variable co-occurrence of amyotrophic lateral sclerosis (ALS) [2]. Formation of insoluble protein deposits, largely composed of ubiquitinated, hyperphosphorylated TAR DNAbinding protein 43 (TDP-43), defines one of the major pathological subtypes of frontotemporal lobar degeneration (FTLD-TDP) as well as ALS patients, introducing a clinicopathological continuum of TDP-43 proteinopathies [3,4,5]. Over the past ten years, considerable progress has been made in unraveling the genetic basis of the FTD-ALS continuum. Mutations in TANK-binding kinase 1 (TBK1), TAR DNA-binding protein 43 (TARDBP), valosin-containing protein (VCP), sequestosome 1 (SQSTM1) and ubiquilin 2 (UBQLN2) can lead to both familial and sporadic forms of FTD and ALS [8]

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