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Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS
"... Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The causes of ALS are poorly understood, although the protein TDP-43 has been suggested to play a critical role in disease pathogenesis. Here we show that Ataxin-2, a polyglutamine (polyQ) protein mutated in spinoc ..."
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Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The causes of ALS are poorly understood, although the protein TDP-43 has been suggested to play a critical role in disease pathogenesis. Here we show that Ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins associate in a complex that depends on RNA. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients. Likewise, TDP-43 shows mislocalization in SCA2. To assess a role in ALS, we analyzed the Ataxin-2 gene (ATXN2) in 915 ALS patients. We found intermediate-length polyQ expansions (27–33 Qs) in ATXN2 significantly associated with ALS. These data establish ATXN2 as a relatively common ALS disease susceptibility gene. Further, these findings indicate that the TDP-43/Ataxin-2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies. Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research,
www.mdpi.com/journal/ijms Drosophila melanogaster as a Model Organism of Brain Diseases
, 2009
"... Abstract: Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experi ..."
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Abstract: Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches.
Drosophila Models of Proteinopathies: the Little Fly that Could
"... Abstract: Alzheimer’s, Parkinson’s, and Huntington’s disease are complex neurodegenerative conditions with high prevalence characterized by protein misfolding and deposition in the brain. Considerable progress has been made in the last two decades in identifying the genes and proteins responsible fo ..."
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Abstract: Alzheimer’s, Parkinson’s, and Huntington’s disease are complex neurodegenerative conditions with high prevalence characterized by protein misfolding and deposition in the brain. Considerable progress has been made in the last two decades in identifying the genes and proteins responsible for several human ‘proteinopathies’. A wide variety of wild type and mutant proteins associated with neurodegenerative conditions are structurally unstable, misfolded, and acquire conformations rich in ß-sheets (ß-state). These conformers form highly toxic self-assemblies that kill the neurons in stereotypical patterns. Unfortunately, the detailed understanding of the molecular and cellular perturbations caused by these proteins has not produced a single disease-modifying therapy. More than a decade ago, several groups demonstrated that human proteinopathies reproduce critical features of the disease in transgenic flies, including protein misfolding, aggregation, and neurotoxicity. These initial reports led to an explosion of research that has contributed to a better understanding of the molecular mechanisms regulating conformational dynamics and neurotoxic cascades. To remain relevant in this competitive environment, Drosophila models will need to expand their flexible, innovative, and multidisciplinary approaches to find new discoveries and translational applications.
Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3
- Hum. Mol. Genet
, 2009
"... Protein cleavage is a common feature in human neurodegenerative disease. Ataxin-3 protein with an expanded polyglutamine (polyQ) repeat causes spinocerebellar ataxia type-3 (SCA3), also called Machado–Joseph disease, and is cleaved in mammalian cells, transgenic mice and SCA3 patient brain tissue. H ..."
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Protein cleavage is a common feature in human neurodegenerative disease. Ataxin-3 protein with an expanded polyglutamine (polyQ) repeat causes spinocerebellar ataxia type-3 (SCA3), also called Machado–Joseph disease, and is cleaved in mammalian cells, transgenic mice and SCA3 patient brain tissue. However, the pathological significance of Ataxin-3 cleavage has not been carefully examined. To gain insight into the significance of Ataxin-3 cleavage, we developed a Drosophila SL2 cell-based model as well as transgenic fly models. Our data indicate that Ataxin-3 protein cleavage is conserved in the fly and may be caspase-dependent as reported previously. Importantly, comparison of flies expressing either wild-type or caspase-site mutant proteins indicates that Ataxin-3 cleavage enhances neuronal loss in vivo. This genetic in vivo confirmation of the pathological role of Ataxin-3 cleavage indicates that therapies target-ing Ataxin-3 cleavage might slow disease progression in SCA3 patients.
degeneration in a Drosophila model of SCA3
, 2009
"... All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. ..."
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All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
ORIGINAL PAPER Mouse Ataxin-3 Functional Knock-Out Model
"... Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Spinocerebellar ataxia 3 (SCA3) is a genetic disorder resulting from the expansion of the CAG repeats in the ATXN3 gene. The pathogenesis of SCA3 is based on the toxic function of the mutant ataxin-3 protei ..."
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Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Spinocerebellar ataxia 3 (SCA3) is a genetic disorder resulting from the expansion of the CAG repeats in the ATXN3 gene. The pathogenesis of SCA3 is based on the toxic function of the mutant ataxin-3 protein, but the exact mechanism of the disease remains elusive. Various types of transgenic mouse models explore different aspects of SCA3 pathogenesis, but a knock-in humanized mouse has not yet been created. The initial aim of this study was to generate an ataxin-3 humanized mouse model using a knock-in strategy. The human cDNA for ataxin-3 containing 69 CAG repeats was cloned from SCA3 patient and introduced into the mouse ataxin-3 locus at exon 2, deleting it along with exon 3 and intron 2. Although the human transgene was inserted correctly, the resulting mice acquired the knock-out properties and did not express ataxin-3 protein in any analyzed tissues, as confirmed by western blot and immunohistochemistry. Analyses of RNA expression revealed that the entire locus consisting of Electronic supplementary material The online version of this article (doi:10.1007/s12017-010-8137-3) contains supplementary material, which is available to authorized users.
3-associated neurodegeneration in Drosophila
, 2011
"... of spinocerebellar ataxia ..."
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ORIGINAL PAPER Spinocerebellar Ataxias in Brazil—Frequencies and Modulating Effects of Related Genes
, 2013
"... Abstract This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neuro-logical findings. Patien ..."
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Abstract This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neuro-logical findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capil-lary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2
1 © 2009 The Author(s)
, 2009
"... This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ..."
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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
Drosophila models reveal novel insights into mechanisms underlying neurodegeneration
"... The SAGA chromatin modifyingcomplex functions as a transcrip-tional coactivator for a large number of genes, and SAGA dysfunction has been linked to carcinogenesis and neurodegen-erative disease. The protein complex is comprised of approximately 20 subunits, arranged in a modular fashion, and includ ..."
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The SAGA chromatin modifyingcomplex functions as a transcrip-tional coactivator for a large number of genes, and SAGA dysfunction has been linked to carcinogenesis and neurodegen-erative disease. The protein complex is comprised of approximately 20 subunits, arranged in a modular fashion, and includes 2 enzymatic subunits: the Gcn5 acetyltransferase and the Non-stop deu-biquitinase. As we learn more about SAGA, it becomes evident that this com-plex functions through sophisticated mechanisms that support very precise regulation of gene expression. Here we describe recent findings in which a Dro-sophila loss-of-function model revealed novel mechanisms for regulation of SAGA-mediated histone H2B deubiqui-tination. This model also yielded novel and surprising insights into mechanisms that underlie progressive neurodegenera-tive disease. Lastly, we comment on the utility of Drosophila as a model for neu-rodegenerative disease through which crucial and conserved mechanisms may be revealed.
