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  1. Article ; Online: Mouse models of spinocerebellar ataxia type 3 (Machado-Joseph disease).

    Colomer Gould, Veronica F

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

    2012  Volume 9, Issue 2, Page(s) 285–296

    Abstract: Machado-Joseph disease, also called spinocerebellar ataxia type 3 (MJD/SCA3), is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a pathological polyglutamine stretch (mutant ataxin-3). Seven transgenic mouse models expressing ...

    Abstract Machado-Joseph disease, also called spinocerebellar ataxia type 3 (MJD/SCA3), is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a pathological polyglutamine stretch (mutant ataxin-3). Seven transgenic mouse models expressing full-length human mutant ataxin-3 throughout the brain have been generated and are compared in this review. They vary in the corresponding transgenic DNA constructs with differences that include the encoded human ataxin-3 isoform(s), number of polyglutamine(s), and the promoter driving transgene expression. The behaviors/signs evaluated in most models are body weight, balance/coordination, locomotor activity, gait, limb position, and age at death. The pathology analyzed includes presence of neuronal intranuclear inclusions, and qualitative evidence of neurodegeneration. On the basis of striking similarities in age-range of detection and number of behavior/sign abnormalities and pathology, all but 1 mouse model could be readily sorted into groups with high, intermediate, and low severity of phenotype. Stereological analysis of neurodegeneration was performed in the same brain regions in 2 mouse models; the corresponding results are consistent with the classification of the mouse models.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Humans ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/pathology ; Machado-Joseph Disease/therapy ; Mice
    Language English
    Publishing date 2012-03-23
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2316693-9
    ISSN 1878-7479 ; 1933-7213
    ISSN (online) 1878-7479
    ISSN 1933-7213
    DOI 10.1007/s13311-012-0117-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Mouse models of Machado-Joseph disease and other polyglutamine spinocerebellar ataxias.

    Colomer Gould, Veronica F

    NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics

    2005  Volume 2, Issue 3, Page(s) 480–483

    Abstract: Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion. Although there is no treatment available at present to cure or delay the onset of MJD, mouse models have been generated ... ...

    Abstract Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion. Although there is no treatment available at present to cure or delay the onset of MJD, mouse models have been generated to facilitate the development of a therapy. In this review, the published reports on mouse models of MJD and other polyglutamine spinocerebellar ataxias are compared. Based on these studies, the following approaches will be discussed as candidate treatments for MJD: 1) interfering with the formation of the mutant ataxin-3 cleavage fragment and possibly aggregate or inclusions, 2) reducing the disease protein nuclear localization, and 3) decreasing mutant ataxin-3 expression in neurons.
    MeSH term(s) Animals ; Ataxin-3 ; Brain Chemistry/physiology ; Cell Nucleus/metabolism ; Humans ; Inclusion Bodies/pathology ; Machado-Joseph Disease/genetics ; Mice ; Nerve Tissue Proteins/biosynthesis ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/physiology ; Nuclear Proteins ; Peptides/genetics ; Peptides/physiology ; Repressor Proteins ; Spinocerebellar Ataxias/genetics ; Transcription Factors
    Chemical Substances Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; Repressor Proteins ; Transcription Factors ; polyglutamine (26700-71-0) ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12) ; Atxn3 protein, mouse (EC 3.4.19.12)
    Language English
    Publishing date 2005-12-13
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2205033-4
    ISSN 1545-5351 ; 1545-5343
    ISSN (online) 1545-5351
    ISSN 1545-5343
    DOI 10.1602/neurorx.2.3.480
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis.

    Williams, Aislinn J / Knutson, Tina M / Colomer Gould, Veronica F / Paulson, Henry L

    Neurobiology of disease

    2008  Volume 33, Issue 3, Page(s) 342–353

    Abstract: Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting ... ...

    Abstract Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting protein), is a central component to the homeostatic mechanisms countering toxic polyQ proteins in the brain. Genetic reduction or elimination of CHIP accelerates disease in transgenic mice expressing polyQ-expanded ataxin-3, the disease protein in Spinocerebellar Ataxia Type 3 (SCA3). In parallel, CHIP reduction markedly increases the level of ataxin-3 microaggregates, which partition in the soluble fraction of brain lysates yet are resistant to dissociation with denaturing detergent, and which precede the appearance of inclusions. The level of microaggregates in the CNS, but not of ataxin-3 monomer, correlates with disease severity. Additional cell-based studies suggest that either of two quality control ubiquitin ligases, CHIP or E4B, can reduce steady state levels of expanded, but not wild-type, ataxin-3. Our results support an aggregation model of polyQ disease pathogenesis in which ataxin-3 microaggregates are a neurotoxic species, and suggest that enhancing CHIP activity is a possible route to therapy for SCA3 and other polyQ diseases.
    MeSH term(s) Aging ; Animals ; Ataxin-3 ; Brain/metabolism ; Brain/pathology ; Cell Line, Tumor ; Heat-Shock Proteins/metabolism ; Humans ; Inclusion Bodies/physiology ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/metabolism ; Machado-Joseph Disease/pathology ; Machado-Joseph Disease/physiopathology ; Mice ; Mice, Transgenic ; Motor Activity ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Nuclear Proteins/chemistry ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptides ; Protein Binding ; Repressor Proteins/chemistry ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Heat-Shock Proteins ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; Repressor Proteins ; polyglutamine (26700-71-0) ; Stub1 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12)
    Language English
    Publishing date 2008-11-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1211786-9
    ISSN 1095-953X ; 0969-9961
    ISSN (online) 1095-953X
    ISSN 0969-9961
    DOI 10.1016/j.nbd.2008.10.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease.

    Nascimento-Ferreira, Isabel / Santos-Ferreira, Tiago / Sousa-Ferreira, Lígia / Auregan, Gwennaëlle / Onofre, Isabel / Alves, Sandro / Dufour, Noëlle / Colomer Gould, Veronica F / Koeppen, Arnulf / Déglon, Nicole / Pereira de Almeida, Luís

    Brain : a journal of neurology

    2011  Volume 134, Issue Pt 5, Page(s) 1400–1415

    Abstract: Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. ... ...

    Abstract Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. Here we investigated the implication of autophagy, the major pathway for organelle and protein turnover, in the accumulation of mutant ataxin-3 aggregates and neurodegeneration found in Machado-Joseph disease and we assessed whether specific stimulation of this pathway could mitigate the disease. Using tissue from patients with Machado-Joseph disease, transgenic mice and a lentiviral-based rat model, we found an abnormal expression of endogenous autophagic markers, accumulation of autophagosomes and decreased levels of beclin-1, a crucial protein in the early nucleation step of autophagy. Lentiviral vector-mediated overexpression of beclin-1 led to stimulation of autophagic flux, mutant ataxin-3 clearance and overall neuroprotective effects in neuronal cultures and in a lentiviral-based rat model of Machado-Joseph disease. These data demonstrate that autophagy is a key degradation pathway, with beclin-1 playing a significant role in alleviating Machado-Joseph disease pathogenesis.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Aged ; Animals ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Ataxin-3 ; Autophagy/genetics ; Autophagy-Related Proteins ; Beclin-1 ; Brain/metabolism ; Brain/pathology ; Carrier Proteins/genetics ; Cell Line, Tumor ; Female ; Flow Cytometry ; Gene Expression Regulation/genetics ; Humans ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/pathology ; Machado-Joseph Disease/physiopathology ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/genetics ; Rats ; Rats, Wistar ; Repressor Proteins/genetics ; Sequestosome-1 Protein ; Transfection/methods ; Trinucleotide Repeat Expansion/genetics
    Chemical Substances ATG16L1 protein, human ; Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; Autophagy-Related Proteins ; BECN1 protein, human ; Beclin-1 ; Carrier Proteins ; Membrane Proteins ; Nerve Tissue Proteins ; Nuclear Proteins ; Repressor Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12)
    Language English
    Publishing date 2011-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awr047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice.

    Colomer Gould, Veronica F / Goti, Daniel / Pearce, Donna / Gonzalez, Guillermo A / Gao, Hong / Bermudez de Leon, Mario / Jenkins, Nancy A / Copeland, Neal G / Ross, Christopher A / Brown, Dale R

    Neurobiology of disease

    2007  Volume 27, Issue 3, Page(s) 362–369

    Abstract: Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ...

    Abstract Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.
    MeSH term(s) Animals ; Ataxin-3 ; Blotting, Western ; Brain/metabolism ; Disease Models, Animal ; Humans ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/metabolism ; Mice ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptide Fragments/metabolism ; Polymerase Chain Reaction ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Transfection
    Chemical Substances Nerve Tissue Proteins ; Nuclear Proteins ; Peptide Fragments ; Repressor Proteins ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12)
    Language English
    Publishing date 2007-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1211786-9
    ISSN 1095-953X ; 0969-9961
    ISSN (online) 1095-953X
    ISSN 0969-9961
    DOI 10.1016/j.nbd.2007.06.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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