Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s40478-017-0432-x
Keywords
C9orf72; FTLD; Nucleolar stress; Dipeptide repeat proteins; Poly(GR); RNA foci
Categories
Funding
- Alzheimer's Research UK (ARUK)
- Motor Neurone Disease Association
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [648716-C9ND]
- Wellcome Trust [098565/Z/12/Z]
- Max Plank Society
- ARUK fellowship
- Leonard Wolfson Clinical Research Training Fellow
- Wellcome Trust Research Training Fellowship [107196/Z/14/Z]
- Alzheimers Research UK [ARUK-PhD2012-29, ARUK-PPG2012B-17, ARUK-PG2016A-6, ARUK-SRF2015-2] Funding Source: researchfish
- Medical Research Council [UKDRI-6003] Funding Source: researchfish
- Motor Neurone Disease Association [Isaacs/Apr13/818-791] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available