Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration
| Autor: | Mizielinska, Sarah, Ridler, Charlotte E., Balendra, Rubika, Thoeng, Annora, Woodling, Nathan S., Grässer, Friedrich A., Plagnol, Vincent, Lashley, Tammaryn, Partridge, Linda, Isaacs, Adrian M. |
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| Rok vydání: | 2017 |
| Předmět: |
Cell Nucleolus/metabolism
Frontal Lobe/metabolism Poly(GR) Intranuclear Inclusion Bodies Neurons/metabolism Fluorescent Antibody Technique Intranuclear Inclusion Bodies/metabolism Dipeptide repeat proteins lcsh:RC346-429 Animals Genetically Modified Imaging Three-Dimensional Stress Physiological C9orf72 Animals Humans In Situ Hybridization Fluorescence lcsh:Neurology. Diseases of the nervous system Neurons DNA Repeat Expansion Microscopy Confocal C9orf72 Protein Research Cell Nucleus Size/genetics RNA foci Proteins Frontal Lobe Cell Nucleus Size Proteins/genetics Drosophila Frontotemporal Lobar Degeneration/genetics Frontotemporal Lobar Degeneration FTLD Nucleolar stress Cell Nucleolus Stress Physiological/genetics |
| Zdroj: | Acta Neuropathol Commun Acta Neuropathologica Communications, Vol 5, Iss 1, Pp 1-11 (2017) Mizielinska, S, Ridler, C E, Balendra, R, Thoeng, A, Woodling, N S, Grässer, F A, Plagnol, V, Lashley, T, Partridge, L & Isaacs, A M 2017, ' Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration ', Acta Neuropathologica Communications, vol. 5, no. 1, 29 . https://doi.org/10.1186/s40478-017-0432-x Acta Neuropathologica Communications |
| Popis: | An intronic GGGGCC expansion in C9orf72 is the most common known cause of both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat expansion leads to the generation of sense and antisense repeat RNA aggregates and dipeptide repeat (DPR) proteins, generated by repeat-associated non-ATG translation. The arginine-rich DPR proteins poly(glycine-arginine or GR) and poly(proline-arginine or PR) are potently neurotoxic and can localise to the nucleolus when expressed in cells, resulting in enlarged nucleoli with disrupted functionality. Furthermore, GGGGCC repeat RNA can bind nucleolar proteins in vitro. However, the relevance of nucleolar stress is unclear, as the arginine-rich DPR proteins do not localise to the nucleolus in C9orf72-associated FTLD/ALS (C9FTLD/ALS) patient brain. We measured nucleolar size in C9FTLD frontal cortex neurons using a three-dimensional, volumetric approach. Intriguingly, we found that C9FTLD brain exhibited bidirectional nucleolar stress. C9FTLD neuronal nucleoli were significantly smaller than control neuronal nucleoli. However, within C9FTLD brains, neurons containing poly(GR) inclusions had significantly larger nucleolar volumes than neurons without poly(GR) inclusions. In addition, expression of poly(GR) in adult Drosophila neurons led to significantly enlarged nucleoli. A small but significant increase in nucleolar volume was also observed in C9FTLD frontal cortex neurons containing GGGGCC repeat-containing RNA foci. These data show that nucleolar abnormalities are a consistent feature of C9FTLD brain, but that diverse pathomechanisms are at play, involving both DPR protein and repeat RNA toxicity. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0432-x) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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