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Ataxin-3 (EC (Machado-Joseph disease protein 1) (Spinocerebellar ataxia type 3 protein) [ATX3] [MJD] [MJD1] [SCA3]


Rescue of ATXN3 neuronal toxicity in [i]Caenorhabditis[/i][i]elegans[/i] by chemical modification of endoplasmic reticulum stress.

Polyglutamine expansion diseases are a group of hereditary neurodegenerative disorders that develop when a CAG repeat in the causative genes is unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats causes hereditary adult-onset neurodegenerative disorders, such as Huntington's disease, dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy and multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited SCA is the type 3 (SCA3), also known as Machado-Joseph disease (MJD), which is an autosomal dominant, progressive neurological disorder. The gene causatively associated with MJD is [i]ATXN3[/i] Recent studies have shown that this gene modulates endoplasmic reticulum (ER) stress. We generated transgenic [i]Caenorhabditis[/i][i]elegans[/i] strains expressing human [i]ATXN3[/i] genes in motoneurons, and animals expressing mutant [i]ATXN3-CAG89[/i] alleles showed decreased lifespan, impaired movement, and rates of neurodegeneration greater than wild-type [i]ATXN3-CAG10[/i] controls. We tested three neuroprotective compounds (Methylene Blue, guanabenz and salubrinal) believed to modulate ER stress and observed that these molecules rescued [i]ATXN3-CAG89[/i] phenotypes. Furthermore, these compounds required specific branches of the ER unfolded protein response (UPR ), reduced global ER and oxidative stress, and polyglutamine aggregation. We introduce new [i]C. elegans[/i] models for MJD based on the expression of full-length [i]ATXN3[/i] in a limited number of neurons. Using these models, we discovered that chemical modulation of the UPR reduced neurodegeneration and warrants investigation in mammalian models of MJD.

MeSH Terms

  • Animals
  • Animals, Genetically Modified
  • Ataxin-3
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cinnamates
  • Endoplasmic Reticulum Stress
  • Guanabenz
  • Humans
  • Longevity
  • Methylene Blue
  • Motor Neurons
  • Mutation
  • Nerve Degeneration
  • Oxidative Stress
  • Paralysis
  • Phenotype
  • Protein Aggregates
  • Repressor Proteins
  • Small Molecule Libraries
  • Thiourea
  • Transgenes
  • Unfolded Protein Response


  • Ataxin 3
  • Caenorhabditis elegans
  • Endoplasmic reticulum stress
  • Guanabenz
  • Polyglutamine

Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4.

Spinocerebellar ataxia type 3 (SCA3) also known as Machado-Joseph Disease (MJD), is one of nine polyglutamine (polyQ) diseases caused by a CAG-trinucelotide repeat expansion within the coding sequence of the ATXN3 gene. There are no disease-modifying treatments for polyQ diseases. Recent studies suggest that an imbalance in histone acetylation may be a key process leading to transcriptional dysregulation in polyQ diseases. Because of this possible imbalance, the application of histone deacetylase (HDAC) inhibitors may be feasible for the treatment of polyQ diseases. To further explore the therapeutic potential of HDAC inhibitors, we constructed two independent preclinical trials with valproic acid (VPA), a promising therapeutic HDAC inhibitor, in both Drosophila and cell SCA3 models. We demonstrated that prolonged use of VPA at specific dose partly prevented eye depigmentation, alleviated climbing disability, and extended the average lifespan of SCA3/MJD transgenic Drosophila. We found that VPA could both increase the acetylation levels of histone H3 and histone H4 and reduce the early apoptotic rate of cells without inhibiting the aggregation of mutant ataxin-3 proteins in MJDtr-Q68- expressing cells. These results collectively support the premise that VPA is a promising therapeutic agent for the treatment of SCA3 and other polyQ diseases.

MeSH Terms

  • Acetylation
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cells, Cultured
  • DNA Repeat Expansion
  • Drosophila
  • Eye
  • Female
  • Histone Deacetylase Inhibitors
  • Histones
  • Humans
  • Life Expectancy
  • Machado-Joseph Disease
  • Mutation
  • Peptides
  • Phenotype
  • Pigmentation
  • Protein Binding
  • Valproic Acid