C9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia

• DOI: 10.1016/j.jbc.2024.105628
• Publication Date: 2024-01-10T07:53:00Z
• Authors: Nemil Bhatt; Nicha Puangmalai; Urmi Sengupta; Cynthia Jerez; Madison Kidd; Shailee Gandhi; Rakez Kayed
• Keywords: C9ORF72

Hexanucleotide repeat expansion in C9orf72 is one of the most common causes amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to production five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among Gly-Arg, Pro-Arg, Gly-Ala form neuronal inclusions that contain aggregates peptides. Several studies have attempted model DPR-associated toxicity using various lengths, which suggests a unique conformation cytotoxic independent length. However, structural characteristics DPR yet be determined. Increasing evidence soluble species, such as oligomers, are main cause proteinopathies, Alzheimer's Parkinson's disease. To investigate ability DPRs aggregate toxic we adopted reductionist approach small 3, 6, 12. This study shows DPRs, particularly glycine-arginine proline-arginine, oligomers exhibit distinct dye-binding properties morphologies. Importantly, also identified dementia postmortem brains morphologically similar those generated recombinantly. demonstrates that, amyloid proteins, toxic, their