RAN (Repeat Associated Non-AUG) antibodies are a group of autoantibodies identified in neurodegenerative disorders, particularly in conditions linked to nucleotide repeat expansions. They are most notably associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by a hexanucleotide repeat expansion (GGGGCC) in the *C9orf72* gene. Unlike traditional antibodies targeting foreign antigens, RAN antibodies recognize aberrant proteins produced through non-canonical translation of expanded RNA repeats, a process termed RAN translation.
In healthy cells, such repetitive sequences are typically not translated into proteins. However, in neurodegenerative diseases, these repeats form secondary RNA structures that recruit ribosomes, initiating translation without an AUG start codon. This generates toxic dipeptide repeat (DPR) proteins (e.g., poly-GA, poly-GR), which aggregate in neurons, disrupting cellular functions and contributing to disease pathology. RAN antibodies specifically detect these misfolded DPR proteins, serving as biomarkers to identify and monitor disease progression.
Their discovery has advanced the understanding of molecular mechanisms in repeat expansion disorders, bridging RNA toxicity and proteinopathy. Clinically, RAN antibodies aid in diagnosing genetic subtypes of ALS/FTD and differentiating them from other neurodegenerative conditions. Research continues to explore their role in therapeutic targeting and prognostic stratification.