Soluble and insoluble dipeptide repeat protein measurements in C9orf72 -frontotemporal dementia brains show regional dif
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(2020) 8:184
Open Access
RESEARCH
Soluble and insoluble dipeptide repeat protein measurements in C9orf72‑frontotemporal dementia brains show regional differential solubility and correlation of poly‑GR with clinical severity Annelies Quaegebeur1*†, Idoia Glaria2,3,4†, Tammaryn Lashley3,5 and Adrian M. Isaacs2,3*
Abstract A C9orf72 repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. One of the suggested pathomechanisms is toxicity from dipeptide repeat proteins (DPRs), which are generated via unconventional translation of sense and antisense repeat transcripts with poly-GA, poly-GP and polyGR being the most abundant dipeptide proteins. Animal and cellular studies highlight a neurotoxic role of poly-GR and poly-PR and to a lesser degree of poly-GA. Human post-mortem studies in contrast have been much less clear on a potential role of DPR toxicity but have largely focused on immunohistochemical methods to detect aggregated DPR inclusions. This study uses protein fractionation and sensitive immunoassays to quantify not only insoluble but also soluble poly-GA, poly-GP and poly-GR concentrations in brain homogenates of FTD patients with C9orf72 mutation across four brain regions. We show that soluble DPRs are less abundant in clinically affected areas (i.e. frontal and temporal cortices). In contrast, the cerebellum not only shows the largest DPR load but also the highest relative DPR solubility. Finally, poly-GR levels and poly-GP solubility correlate with clinical severity. These findings provide the first cross-comparison of soluble and insoluble forms of all sense DPRs and shed light on the distribution and role of soluble DPRs in the etiopathogenesis of human C9orf72-FTD. Keywords: Frontotemporal dementia, Frontotemporal lobar degeneration, C9orf72 mutation, Dipeptide repeat proteins, Poly-GR, Solubility, Meso Scale Discovery
*Correspondence: [email protected]; [email protected] † Annelies Quaegebeur and Idoia Glaria have contributed equally to this work 1 National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK 2 UK Dementia Research Institute at UCL, Cruciform Building, Gower Street, London WC1E 6BT, UK Full list of author information is available at the end of the article
Introduction Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum most often caused by a non-coding hexanucleotide GGG GCCrepeat expansion in the C9orf72 gene [10, 14, 24]. How these repeat expansion mutations mediate neurotoxicity in C9-FTD/ALS disease is a hotly debated topic in the field. Three main mechanisms have been put forward: loss of C9orf72 function and gain of function via toxicity from repeat RNAs and/ or their dipeptide repeat protein products [3]. Sense and
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