Poly(glycine-alanine) protein (Poly-GA)

The Poly(glycine-alanine) (Poly-GA) protein, also known as the GA-RAN protein, is a pathological dipeptide repeat protein (DPR) generated through repeat-associated non-AUG (RAN) translation of the GGGGCC hexanucleotide expansion in the C9orf72 gene. This genetic mutation is the most prevalent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-GA is the most abundant DPR species found in the central nervous system of affected patients, where it forms characteristic neuronal cytoplasmic inclusions. It exerts neurotoxicity by sequestering essential cellular components, such as the 26S proteasome and the transport factor Unc119, leading to impaired protein degradation, endoplasmic reticulum stress, and disrupted nucleocytoplasmic transport. Furthermore, extracellular Poly-GA can be released from neurons and spread to neighboring cells, potentially contributing to the progression of neurodegeneration. Therapeutic efforts are currently focused on using monoclonal antibodies to clear these toxic aggregates or employing antisense oligonucleotides to reduce the production of the underlying repeat-containing transcripts.

Other names

GA-RAN proteinPoly-GAPoly(GA)Glycine-alanine dipeptide repeat proteinC9orf72 RAN-translated proteinPoly-GA DPR

Passive immunotherapy using monoclonal antibodies to bind and promote the clearance of Poly-GA aggregates, prevent cell-to-cell spreading, and restore proteasomal activity and cellular homeostasis.