C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology
Year: 2024
Type: article
Abstract: Proteinaceous inclusions formed by C9orf72 derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ~50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-centre appearance, resembling anisosomes formed by aberrant TDP-43 species, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without the activation of stress response. Cytoplasmic poly-PR aggregates that formed under prolonged light stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Our data suggest that poly-PR anisotropic condensation in the nucleus, causative of nuclear TDP-43 dysfunction, may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates may represent a more common cellular pathology in neurodegeneration than previously thought. Highlights - Optogenetics can be used to model C9orf72 DPR condensation in cultured cells. - Opto-PR forms hollow nuclear condensates, and RNA limits their growth by fusion. - Opto-PR condensation leads to stress-independent TDP-43 pathology in the nucleus. - Cytoplasmic poly-PR assemblies are persistent and selectively sequester TDP-43. Graphical abstract
Source: iScience
Institution: University of Sheffield
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,150
Awards: G1096621605, Mechanistic studies of ALS-causative mutations and RNP-focussed drug discovery using in vitro reconstitution of RNP complexes, G1428984192, RNA-protein complexes in health and disease and their therapeutic targeting, G2430957586, Understanding the crosstalk between spatially separated RNP granules during cellular stress responses, An Airyscan 2 confocal laser scanning microscope for the Wolfson Light Microscopy Facility, G4949859070, G5528044416, G5791003530, G7037653947, G7780817649, Structural and functional investigation of the SRSF1-mediated nuclear export of mRNAs
OpenAlex ID: W4402546382