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

Nemil Bhatt, Nicha Puangmalai, Urmi Sengupta, Cynthia Jerez, Madison Kidd, Shailee Gandhi, Rakez Kayed

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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

Original languageEnglish (US)
Article number105628
JournalJournal of Biological Chemistry
Volume300
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • ALS
  • C9orf72
  • FTD
  • amyloids
  • dipeptide protein repeats
  • neurodegeneration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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