Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism

Broeck, Lies Vanden; Kleinberger, Gernot; Chapuis, Julien; Gistelinck, Marc; Amouyel, Philippe; Broeckhoven, Christine Van; Lambert, Jean‐Charles; Callaerts, Patrick; Dermaut, Bart

doi:10.1016/j.neurobiolaging.2014.09.001

Cited by 25 publications

(18 citation statements)

References 46 publications

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“…To this end, we generated TDP-43 KO cell lines that stably expressed 8 different disease causing TDP-43 mutations ( Fig. 5A; A90V, P112H, D169G, K263E, A315T, Q331K, M337V, A382T) (Banks et al, 2008;Corrado et al, 2009;Gitcho et al, 2008;Kabashi et al, 2010;Kabashi et al, 2008;Kovacs et al, 2009;Moreno et al, 2015;Rutherford et al, 2008;Sreedharan et al, 2008;Vanden Broeck et al, 2015;Winton et al, 2008). After confirming that each mutant was expressed at similar levels to the WT TDP-43 ( Fig.…”

Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 99%

“…whereby TDP-43 mutations give rise to neurodegenerative disease, it still remains unclear to what extent these mutations exert pathogenic effects via gain-of-function versus lossof-function mechanisms (Kabashi et al, 2010;Orru et al, 2016;Vanden Broeck et al, 2015). We thus took advantage of robust TDP-43 KO phenotypes to assess the functionality of a panel of neurodegenerative disease causing TDP-43 mutants (Fig.…”

Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 99%

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Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Roczniak-Ferguson

Ferguson

2019

Preprint

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TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in multiple neurodegenerative diseases. Although the loss of normal TDP-43 functions likely contributes to disease pathogenesis, the cell biological consequences of human TDP-43 depletion are not well understood. We therefore generated human TDP-43 knockout cells and subjected them to parallel cell biological and transcriptomic analyses. These efforts yielded three important discoveries. First, complete loss of TDP-43 resulted in widespread morphological defects related to multiple organelles including: Golgi, endosomes, lysosomes, mitochondria and the nuclear envelope. Second, we identified a new role for TDP-43 in controlling mRNA splicing of Nup188 (nuclear pore protein). Third, analysis of multiple amyotrophic lateral sclerosis (ALS) causing TDP-43 mutations revealed a broad ability to support splicing of TDP-43 target genes. However, as some TDP-43 disease causing mutants failed to support the regulation of specific target transcripts, our results raise the possibility of mutation-specific loss-of-function contributions to disease pathology.

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Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 99%

Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 99%

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Roczniak-Ferguson

Ferguson

2019

Preprint

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“…Pieces of research of the TDRDBP gene have identified 44 different mutations according to Alzheimer Disease& Frontotemporal Dementia Mutation Database, but only rare mutation P.Ala90val of unclear pathogenic nature is reported to relate with AD affecting the nuclear localization signal of TDP-43 [7,9,10]. Recently, a study has suggested that pathogenic TARDBP mutations have partial loss-of-function properties and the p.A90V increases AD risk by this mechanism [11]. Most of the TARDBP mutations are autosomal-dominant missense mutations and are observed only in ALS with an estimated frequency of 4 % in familial ALS patients and~1.5 % in sporadic ALS with or without associated FTLD [12,13].…”

Section: Biochemical Characters Of Tdp-43mentioning

confidence: 99%

The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

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The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.

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“…Drosophila happens to be a very useful model for addressing this issue. The rationale consists in performing functional transcomplementation experiments in Drosophila , as successfully illustrated for VUS in the TARDBP gene [ 38 ]. TARDBP encodes the TDP-43 protein, which forms cytoplasmic inclusions in patients with the most frequent form of frontotemporal dementia (FTD) and most forms of amyotrophic lateral sclerosis (ALS) and in 60% of patients with AD.…”

Section: Drosophila For Screening Gwas-defined Genesmentioning

confidence: 99%

Using High-Throughput Animal or Cell-Based Models to Functionally Characterize GWAS Signals

2018

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Purpose of ReviewThe advent of genome-wide association studies (GWASs) constituted a breakthrough in our understanding of the genetic architecture of multifactorial diseases. For Alzheimer’s disease (AD), more than 20 risk loci have been identified. However, we are now facing three new challenges: (i) identifying the functional SNP or SNPs in each locus, (ii) identifying the causal gene(s) in each locus, and (iii) understanding these genes’ contribution to pathogenesis.Recent FindingsTo address these issues and thus functionally characterize GWAS signals, a number of high-throughput strategies have been implemented in cell-based and whole-animal models. Here, we review high-throughput screening, high-content screening, and the use of the Drosophila model (primarily with reference to AD).SummaryWe describe how these strategies have been successfully used to functionally characterize the genes in GWAS-defined risk loci. In the future, these strategies should help to translate GWAS data into knowledge and treatments.

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Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism

Cited by 25 publications

References 46 publications

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

The Role of TDP-43 in Alzheimer’s Disease

Using High-Throughput Animal or Cell-Based Models to Functionally Characterize GWAS Signals

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