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  Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration

Mizielinska, S., Ridler, C. E., Balendra, R., Thoeng, A., Woodling, N. S., Grasser, F. A., et al. (2017). Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun, 5(1), 29. doi:10.1186/s40478-017-0432-x.

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Mizielinska, S., Author
Ridler, C. E., Author
Balendra, R., Author
Thoeng, A., Author
Woodling, N. S., Author
Grasser, F. A., Author
Plagnol, V., Author
Lashley, T., Author
Partridge, L.1, Author           
Isaacs, A. M., Author
Affiliations:
1Department Partridge - Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_1942287              

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Free keywords: Animals Animals, Genetically Modified Cell Nucleolus/*metabolism/*pathology Cell Nucleus Size/genetics/physiology DNA Repeat Expansion Drosophila Fluorescent Antibody Technique Frontal Lobe/metabolism/pathology Frontotemporal Lobar Degeneration/genetics/*metabolism/*pathology Humans Imaging, Three-Dimensional In Situ Hybridization, Fluorescence Intranuclear Inclusion Bodies/metabolism/pathology Microscopy, Confocal Neurons/metabolism/pathology Proteins/genetics/*metabolism Stress, Physiological/genetics/physiology C9orf72 Dipeptide repeat proteins Ftld Nucleolar stress Poly(GR) RNA foci
 Abstract: 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.

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 Dates: 2017-04-182017
 Publication Status: Issued
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 Identifiers: Other: 28420437
DOI: 10.1186/s40478-017-0432-x
ISSN: 2051-5960 (Electronic)2051-5960 (Linking)
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Title: Acta Neuropathol Commun
Source Genre: Journal
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Pages: - Volume / Issue: 5 (1) Sequence Number: - Start / End Page: 29 Identifier: -