Dataset Information

Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.

ABSTRACT: There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.

SUBMITTER: Cushman-Nick M

PROVIDER: S-EPMC3764203 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.

Cushman-Nick Mimi M Bonini Nancy M NM Shorter James J

PLoS genetics 20130905 9

There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly ...[more]

PMID: 24039611

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Project description:At least 40 human diseases are associated with repeat expansions; yet, the mutational origin and instability mechanisms remain unknown for most of them. Previously, genetic epidemiology and predisposing backgrounds for the instability of some expanding loci have been studied in different populations through the analysis of diversity flanking the respective pathogenic repeats. Here, we aimed at developing a pipeline to assess disease-associated haplotypes at oligonucleotide repeat loci, combining analysis of single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs). Machado-Joseph disease (MJD/SCA3), the most frequent dominant ataxia worldwide, was used as an example of a detailed procedure. Thus, to identify genetic backgrounds that segregate with expanded/mutated alleles in MJD, we selected a set of 26 SNPs and 7 STRs flanking the causative CAG repeat. Key criteria and steps for this selection are described, and included (1) haplotype blocks minimizing the occurrence of recombination (for SNPs); and (2) match scores to increase potential for polymorphic information content of repetitive sequences found in Tandem Repeats Finder (for STRs). To directly assess SNP haplotypes in phase with MJD expansions, we optimized a strategy with preferential amplification of normal over expanded alleles, in addition to SNP allele-specific amplifications; this allowed the identification of disease-associated SNP haplotypes, even when only the proband is available in a given family. To infer STR haplotypes, we optimized a multiplex PCR, including 7 STRs plus the MJD_CAG repeat, followed by analysis of segregation or the use of the PHASE software. This protocol is a ready-to-use tool to assess MJD haplotypes in different populations. The pipeline designed can be used to assess disease-associated haplotypes in other repeat-expansion diseases. This should be of great utility to study (1) genetic epidemiology (population-of-origin, age and spreading routes of mutations) and (2) mechanisms responsible for de novo expansions, in these neurological diseases; (3) to detect predisposing haplotypes and (4) phenotype modifiers; (5) to help solving cases of apparent homoallelism (two same-size normal alleles) in diagnosis; and (6) to identify the best targets for the development of allele-specific therapies in ethnically diverse patient populations.

Dataset Information

Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.

Publications

Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.

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