A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration.

Daniel A Solomon ,Tibor Hortobágyi,Alan Stepto,Matthias Soller,Boris Rogelj,Jonah Dearlove,Adel Boudi,Manolis Fanto,Claire Troakes,Wing Hei Au,Frank Hirth,Paraskevi Tziortzouda,Greta Spinelli,Anjeet Rekhi,Christopher E Shaw ,Bradley N Smith ,Danielle C Diaper ,Dickon M Humphrey ,Richard L Hall ,Youn‐Bok Lee ,Jean‐Marc Gallo ,Richard B Parsons ,Yoshiyuki Adachi ,Jéssika Cristina Bridi

doi:10.1093/brain/awy241

Abstract

Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-α2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.

Highlights

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases for which no cure is available (Van Langenhove et al, 2012; Ling et al, 2013)
dipeptide-repeat proteins (DPRs) expression profiles were dependent on the 50 linker sequence for G4C2 repeats of different length (Table 1) and independent of a near-cognate CUG codons 50 of the repeats (Supplementary Fig. 1D), which has been recently related to G4C2 repeat-associated non-ATG (RAN) translation (Green et al, 2017; Tabet et al, 2018)
Our findings reported here provide experimental and pathological evidence for a sequence of events in which DPR-triggered TDP-43 accumulation causes KPNA pathology that precedes chromosome 9 open reading frame 72 (C9orf72)-related neurodegeneration (Fig. 6C)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases for which no cure is available (Van Langenhove et al, 2012; Ling et al, 2013). In addition to genetic evidence, proteinaceous inclusions of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) are a histopathological hallmark of 97% of ALS and 45% of FTD cases (Ling et al, 2013). TDP-43 shuttles between the nucleus and cytoplasm where it functions in mRNA stability, translation and transport (Lee et al, 2011; Ederle and Dormann, 2017) Imbalance of this process leads to cytoplasmic accumulation and in turn nuclear depletion of TDP-43 and assembly into aggregates of phosphorylated and ubiquitinated C-terminal fragments that characterize the progressive and end stages of disease (Arai et al, 2006; Neumann et al, 2006)

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