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General Information
Name
polyglutamine diseases, polyQ models
FlyBase ID
FBhh0000001
Disease Ontology Term
Parent Disease
OMIM
Overview

A number of inherited disorders are caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. This report describes the "polyQ-only" model systems developed in Drosophila, using UAS constructs driving a run of CAG repeats of variable length, flanked by sequence encoding a few amino acids. Information on Drosophila models of specific CAG-repeat diseases (such as Huntington disease and several of the spinocerebellar ataxia subtypes) can be found in separate reports (see "Related diseases" section, below). Runs of short nucleotide repeats may also result in pathologies effected via the transcript(s) of a gene, rather than the protein products. Work in Drosophila addressing this phenomenon is described in a separate disease reports; see RNA-repeat diseases (FBhh0000059).

Data relevant to the "polyQ only" systems are also presented in the FlyBase record for the synthetic gene Zzzz\CAG. Numerous transgenic constructs have been created, typically using a GAL4 system UAS element followed by a run of CAG repeats (encoding polyglutamine) of variable length flanked by sequence encoding a few amino acids; often the flanking sequences include an epitope tag, such as HA, Myc or FLAG. The GAL4-UAS system is used to drive expression of the polyQ polypeptide in neural tissues, typically in the developing eye or in all developing neurons; expression in glial cells has also been characterized.

[updated Oct. 2016 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: polyglutamine diseases, polyQ models
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Polyglutamine expansions appear to be a causative factor in a number of neurodegenerative diseases.

Genetics

Caused by an expanded trinucleotide repeat (CAG)n, encoding glutamine; described as CAG repeat at nucleotide level; described as polyglutamine or polyQ at protein level.

Cellular phenotype and pathology

Intracellular aggregates of mutant proteins is a pathology common to the polyglutamine diseases and it has been assumed that aggregate formation contributes to disease development. A more recent model postulates that large intracellular inclusions are cytoprotective and that it is smaller oligomers that escape aggregation that underlie pathogenesis.

Molecular information

Using assays in flies, it was concluded that majority of the phenotype produced by CAG-repeats within the translated portion of an mRNA is likely to be the result of the polyglutamine peptide itself and not the repeat-containing RNA.

This report describes the "polyQ-only" model systems developed in Drosophila, and includes only results shown to be or thought to be effected by the polyglutamine-containing polypeptide (FBrf0187723, FBrf0213942).

Multiple lines of evidence support the hypothesis that polyQ-induced protein misfolding and the resultant stress on protein homeostatic pathways play a central role in pathogenesis. Well-supported genetic modifiers include heat-shock proteins and other chaperones, ubiquitin proteasome pathway (UPP) proteins, and proteins that play a role in autophagy. The unique sensitivity of certain neural cell types to polyQ diseases may be due to differences in these protein quality control processes.

External links
    Disease synonyms
    polyQ expansion diseases
    CAG repeat diseases
    CAG triplet repeat disorders
    trinucleotide repeat disorders
    polyglutamine diseases
    Ortholog Information
    Human gene(s) in FlyBase
      Other mammalian ortholog(s) used
        D. melanogaster Gene Information (0)
        Synthetic Gene(s) Used (1)
        Summary of Physical Interactions (0 groups)
        Alleles Reported to Model Human Disease (Disease Ontology) (18 alleles)
        Models Based on Experimental Evidence ( 15 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 12 )
        Allele
        Disease
        Interaction
        References
        is exacerbated by nejP
        is ameliorated by nejEP1149
        is ameliorated by nejEP1179
        is exacerbated by Khc9
        is ameliorated by ZwUAS.cLa
        is ameliorated by DnaJ-1UAS.cKb
        Genetic Tools, Stocks and Reagents
        Sources of Stocks
        Contact lab of origin for a reagent not available from a public stock center.
        Bloomington Stock Center Disease Page
        Selected mammalian transgenes
        Allele
        Transgene
        Publicly Available Stocks
        Selected Drosophila transgenes
        Allele
        Transgene
        Publicly Available Stocks
        RNAi constructs available
        Allele
        Transgene
        Publicly Available Stocks
        Selected Drosophila classical alleles
        Allele
        Allele class
        Mutagen
        Publicly Available Stocks
        References (68)