Glycine-alanine dipeptide repeat protein (poly-GA) (poly-GA)

The glycine-alanine dipeptide repeat protein (poly-GA) is an abnormal protein produced via repeat-associated non-AUG (RAN) translation from the sense strand of the hexanucleotide GGGGCC repeat expansion in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-GA is highly aggregation-prone, rapidly forming flat ribbon-type amyloid fibrils with a characteristic cross-β sheet structure, as shown by electron microscopy, X-ray scattering, and amyloid dyes like Thioflavin T and Congo red. These aggregates accumulate as ubiquitin- and p62-positive inclusions in neuronal cells, particularly in the cerebellum and hippocampus, and exhibit neurotoxicity, disrupting cellular proteostasis by interfering with the ubiquitin-proteasome system (UPS). Poly-GA fibrils also demonstrate cell-to-cell transmission properties, propagating toxicity similar to prions in neurodegenerative contexts. Among C9orf72-derived dipeptide repeats (DPRs) like poly-GR, poly-PR, and poly-GP, poly-GA shows the strongest tendency for insoluble inclusion body formation, dependent on repeat length (e.g., prominent with 15+ repeats), contributing substantially to neurodegeneration in c9FTD/ALS. No approved drugs directly target poly-GA, but its properties inform therapeutic strategies aimed at reducing DPR production or aggregation.

Other names

poly-glycine-alanineGA DPR(GA)_n