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