Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Neurotherapeutics ; 9(2): 285-96, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22451301

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.


Subject(s)
Disease Models, Animal , Machado-Joseph Disease/genetics , Machado-Joseph Disease/pathology , Animals , Animals, Genetically Modified , Humans , Machado-Joseph Disease/therapy , Mice
2.
Brain ; 134(Pt 5): 1400-15, 2011 May.
Article in English | MEDLINE | ID: mdl-21478185

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.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Autophagy/genetics , Machado-Joseph Disease/genetics , Membrane Proteins/metabolism , Mutation/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Adaptor Proteins, Signal Transducing/genetics , Aged , Animals , Apoptosis Regulatory Proteins/genetics , Ataxin-3 , 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/pathology , Machado-Joseph Disease/physiopathology , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Rats , Rats, Wistar , Sequestosome-1 Protein , Transfection/methods , Trinucleotide Repeat Expansion/genetics
3.
Neurobiol Dis ; 33(3): 342-53, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19084066

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.


Subject(s)
Brain/metabolism , Machado-Joseph Disease/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nuclear Proteins/metabolism , Peptides , Repressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Aging , Animals , Ataxin-3 , Brain/pathology , Cell Line, Tumor , Heat-Shock Proteins/metabolism , Humans , Inclusion Bodies/physiology , Machado-Joseph Disease/genetics , Machado-Joseph Disease/pathology , Machado-Joseph Disease/physiopathology , Mice , Mice, Transgenic , Motor Activity , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Protein Binding , Repressor Proteins/chemistry , Repressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics
4.
Neurobiol Dis ; 27(3): 362-9, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17632007

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.


Subject(s)
Brain/metabolism , Machado-Joseph Disease/genetics , Machado-Joseph Disease/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Peptide Fragments/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Animals , Ataxin-3 , Blotting, Western , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Mutation , Polymerase Chain Reaction , Transfection
5.
NeuroRx ; 2(3): 480-3, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16389311

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.


Subject(s)
Machado-Joseph Disease/genetics , Peptides/genetics , Peptides/physiology , Spinocerebellar Ataxias/genetics , Animals , Ataxin-3 , Brain Chemistry/physiology , Cell Nucleus/metabolism , Humans , Inclusion Bodies/pathology , Mice , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Nuclear Proteins , Repressor Proteins , Transcription Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...