Dipeptide Repeat derived from C9orf72 Hexanucleotide Expansions Forms Amyloids or natively unfolded structures in vitro

Laurent Brasseur (1) , Audrey Coens (1) , Jehan Waeytens (2, 3) , Ronald Melki (1) , Luc Bousset (1)

1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
2 LCPO - Laboratoire de Chimie Physique D'Orsay
3 ULB - Université libre de Bruxelles

The abnormal repetition of the hexanucleotide GGGGCC within the C9orf72 gene isthe most common genetic cause of both Amyotrophic Lateral Sclerosis (ALS) andFrontotemporal Dementia (FTD). Different hypothesis have been proposed to explain thepathogenicity of this mutation. Among them, the production of aberrant proteins calledDipeptide Repeat Proteins (DPR) from the repeated sequence. Those proteins are of interest,as they are toxic and form insoluble deposits in patient brains. In this study, we characterizethe structural features of three different DPR encoded by the hexanucleotide repeat GGGGCC,namely poly-GA, poly-GP and poly-PA. We show that DPR are natively unstructured proteinsbut that only poly-GA forms in vitro fibrillary aggregates. Poly-GA fibrils are of amyloid natureas revealed by their high content in beta sheets. They neither bind Thioflavin T nor Primuline,the commonly used amyloid fluorescent dyes. Remarkably, not all of the poly-GA primarystructure was part of fibrils amyloid core.

Domains: Biochemistry [q-bio.BM]; Structural Biology [q-bio.BM]; Neurons and Cognition [q-bio.NC]

Laurent Brasseur, Audrey Coens, Jehan Waeytens, Ronald Melki, Luc Bousset. Dipeptide Repeat derived from C9orf72 Hexanucleotide Expansions Forms Amyloids or natively unfolded structures in vitro. Biochemical and Biophysical Research Communications, 2020, ⟨10.1016/j.bbrc.2020.03.108⟩. ⟨cea-02529282⟩