C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology

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 m...

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Published in:iScience 2024-10, Vol.27 (10), p.110937, Article 110937
Main Authors: Hodgson, Rachel E., Rayment, Jessica A., Huang, Wan-Ping, Sanchez Avila, Anna, Ellis, Brittany C.S., Lin, Ya-Hui, Soni, Nikita, Hautbergue, Guillaume M., Shelkovnikova, Tatyana A.
Format: Article
Language:English
Subjects:
Biochemistry
Cell biology
Molecular biology
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Summary: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 including human motor neurons, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-center appearance, resembling TDP-43 anisosomes, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without stress response activation. Cytoplasmic poly-PR aggregates forming under prolonged opto-stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Thus, poly-PR condensation accompanied by nuclear TDP-43 dysfunction may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates of disease-linked proteins may represent a common molecular species in neurodegenerative disease. [Display omitted] •Optogenetics can be used to model C9orf72 DPR condensation in neurons•Opto-PR forms hollow-center nuclear condensates, and RNA limits their growth•Opto-PR condensation elicits stress-independent nuclear TDP-43 pathology•Cytoplasmic poly-PR assemblies are persistent and selectively sequester TDP-43 Biochemistry; Molecular biology; Cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.110937