Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila

Miguel, Laëtitia; Avequin, Tracey; Delarue, Morgane; Feuillette, Sébastien; Frébourg, Thierry; Campion, Dominique; Lecourtois, Magalie

doi:10.1016/j.neurobiolaging.2011.10.008

Cited by 54 publications

(26 citation statements)

References 31 publications

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“…WT hFUS is primarily localized in the nucleus of these cells. These results suggest that the toxicity observed from WT hFUS overexpression is the result of nuclear, not cytoplasmic function (Miguel et al, 2012), consistent with the recently proposed cause of TDP-43-associated toxicity (Kim et al, 2012). …”

Section: 0 Drosophila Models Of Alssupporting

confidence: 88%

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A fruitful endeavor: Modeling ALS in the fruit fly

Casci

Pandey

2015

Brain Research

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For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research.

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Section: 0 Drosophila Models Of Alssupporting

confidence: 88%

“…Over time, there is an accumulation of insoluble, non-aggregated WT hFUS when expressed in adult neurons that coincides with neurodegenerative phenotypes (Miguel et al, 2012). Reducing insoluble hFUS levels with coexpression of the chaperone protein, HSPA1L, reduces eye degeneration and improves lifespan.…”

Section: 0 Drosophila Models Of Alsmentioning

confidence: 99%

A fruitful endeavor: Modeling ALS in the fruit fly

Casci

Pandey

2015

Brain Research

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“…Importantly, since its first introduction in 2007 by one of us to modelize successfully SCA7 pathology (Latouche et al, 2007), the elavGS system has been used by several labs to study Drosophila neurodegenerative disease models. This includes a model for Aβ induced pathology (Sofola et al, 2010; Rogers et al, 2012), models for polyQ diseases (Spinobulbar muscular atrophy (SBMA; Pandey et al, 2007), and SCA3 (Martin-Lannerée et al, 2006), model for Parkinson disease (Kanao et al, 2010) as well as the two FTD models used in this study (FUS and TBP43; Lanson et al, 2011; Miguel et al, 2011, 2012). Therefore, it is now widely accepted that inducible elavGS models are adequate to express disease proteins in adult CNS with pathological consequences that mimic the disease.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore TDP-43 and FUS are good candidates for a direct regulation of miRNA expression. Expression of wild-type form of TDP-43 or FUS proteins was achieved using transgenic Drosophila lines (UAS-TDP-43, UAS-FUS) previously described and characterized (Miguel et al, 2011, 2012). miRNA expression profiling was performed in two independent samples of total RNA extracted from heads of flies expressing (RU200) or not (RU0) TDP-43 or FUS proteins.…”

Section: Resultsmentioning

confidence: 99%

“…The Atxn3 lines were generated by cloning of the full length Atxn3 coding region described in (Mueller et al, 2009) inside a pAttB-UAS vector followed by insertion at the Att40 landing site by standard ways. For FTLD diseases the following transgenic Drosophila strains were used in this study: UAS-TauV337M (Wittmann et al, 2001); UAS-TDP-43 (Miguel et al, 2011); and UAS-FUS (Miguel et al, 2012). Drosophila strains were raised on standard cornmeal-yeast agar medium.…”

Section: Methodsmentioning

confidence: 99%

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Lack of miRNA Misregulation at Early Pathological Stages in Drosophila Neurodegenerative Disease Models

Reinhardt¹,

Feuillette²,

Cassar³

et al. 2012

Front. Gene.

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Late onset neurodegenerative diseases represent a major public health concern as the population in many countries ages. Both frequent diseases such as Alzheimer disease (AD, 14% incidence for 80–84 year-old Europeans) or Parkinson disease (PD, 1.4% prevalence for >55 years old) share, with other low-incidence neurodegenerative pathologies such as spinocerebellar ataxias (SCAs, 0.01% prevalence) and frontotemporal lobar degeneration (FTLD, 0.02% prevalence), a lack of efficient treatment in spite of important research efforts. Besides significant progress, studies with animal models have revealed unexpected complexities in the degenerative process, emphasizing a need to better understand the underlying pathological mechanisms. Recently, microRNAs (miRNAs), a class of small regulatory non-coding RNAs, have been implicated in some neurodegenerative diseases. The current data supporting a role of miRNAs in PD, tauopathies, dominant ataxias, and FTLD will first be discussed to emphasize the different levels of the pathological processes which may be affected by miRNAs. To investigate a potential involvement of miRNA dysregulation in the early stages of these neurodegenerative diseases we have used Drosophila models for seven diseases (PD, 3 FTLD, 3 dominant ataxias) that recapitulate many features of the human diseases. We performed deep sequencing of head small RNAs after 3 days of pathological protein expression in the fly head neurons. We found no evidence for a statistically significant difference in miRNA expression in this early stage of the pathological process. In addition, we could not identify small non-coding CAG repeat RNAs (sCAG) in polyQ disease models. Thus our data suggest that transcriptional deregulation of miRNAs or sCAG is unlikely to play a significant role in the initial stages of neurodegenerative diseases.

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TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

2013

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Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.

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Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila

Cited by 54 publications

References 31 publications

A fruitful endeavor: Modeling ALS in the fruit fly

A fruitful endeavor: Modeling ALS in the fruit fly

Lack of miRNA Misregulation at Early Pathological Stages in Drosophila Neurodegenerative Disease Models

TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

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