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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, *
* Corresponding author
1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
MIRCEN - Service MIRCEN : DRF/JACOB, CNRS - Centre National de la Recherche Scientifique : UMR 9199
Abstract : The abnormal repetition of the hexanucleotide GGGGCC within the C9orf72 gene is the most common genetic cause of both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Different hypothesis have been proposed to explain the pathogenicity of this mutation. Among them, the production of aberrant proteins called Dipeptide 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 characterize the 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 proteins but that only poly-GA forms in vitro fibrillary aggregates. Poly-GA fibrils are of amyloid nature as 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 primary structure was part of fibrils amyloid core.
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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, Elsevier, 2020, ⟨10.1016/j.bbrc.2020.03.108⟩. ⟨cea-02529282⟩

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