Expression of human FUS protein in Drosophila leads to progressive neurodegeneration

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Tsinghua University, Beijing, China.
Protein & Cell (Impact Factor: 3.25). 06/2011; 2(6):477-86. DOI: 10.1007/s13238-011-1065-7
Source: PubMed


Mutations in the Fused in sarcoma/Translated in liposarcoma gene (FUS/TLS, FUS) have been identified among patients with amyotrophic lateral sclerosis (ALS). FUS protein aggregation is a major pathological hallmark of FUS proteinopathy, a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies. We prepared transgenic Drosophila expressing either the wild type (Wt) or ALS-mutant human FUS protein (hFUS) using the UAS-Gal4 system. When expressing Wt, R524S or P525L mutant FUS in photoreceptors, mushroom bodies (MBs) or motor neurons (MNs), transgenic flies show age-dependent progressive neural damages, including axonal loss in MB neurons, morphological changes and functional impairment in MNs. The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy, representing the first stable animal model for this group of devastating diseases.

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Available from: Li Zhu, Oct 17, 2014
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    • "Overexpression of mutant FUS in a transgenic mouse model develops progressive paralysis due to motor axonal degeneration and neuronal loss in the cortex and hippocampus [32]. In transgenic Drosophila model, it has been observed age-dependent progressive motor neuron damage when Wt, R524S or P525L mutant FUS are over-expressed in photoreceptors [33]. In addition, over-expressing WT or mutant FUS C. elegant models and knocking down endogenous FUS Zebrafish models are both used to study the mechanism of FUS mediated motor neurodegeneration [27]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
    Full-text · Article · Aug 2013 · Molecular Neurodegeneration
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    • "Following overexpression in eukaryotic cells, WT FUS localizes to the nucleus, whereas FUS proteins carrying ALS mutations in the NLS form cytoplasmic aggregates, thereby mimicking human disease [116, 196]. This cytoplasmic relocalization is observed in some but not all FUS animal models reported to date [25, 32, 42, 86, 119, 142, 198, 203, 211] (Supplementary Table). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1125-6) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2013 · Acta Neuropathologica
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    • "Cytosolic mislocalization and deposition of the FET proteins may also create a toxic 'gain-of-function', e.g. through aberrant binding of cytosolic RNA targets (Hoell et al., 2011) or altered protein–protein interactions. Overexpression of FUS or mutant FUS in yeast and various model animals indeed causes toxicity and recapitulates certain disease features (Chen et al., 2011; Fushimi et al., 2011; Huang et al., 2011; Ju et al., 2011; Kabashi et al., 2011; Kryndushkin et al., 2011; Lanson et al., 2011; Murakami et al., 2012; Sun et al., 2011; Vaccaro et al., 2012; Verbeeck et al., 2012). However under physiological conditions, FUS levels appear to be tightly regulated by an autoregulatory mechanism (Lagier-Tourenne et al., 2012), suggesting that overexpression models should be interpreted with caution. "
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    ABSTRACT: Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family.
    Full-text · Article · Apr 2013 · Molecular and Cellular Neuroscience
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