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Mizielinska et al. Acta Neuropathologica Communications (2017) 5:29 DOI ten.1186/s40478-017-0432-xRESEARCHOpen AccessBidirectional BTNL2 Protein Mouse nucleolar dysfunction in C9orf72 frontotemporal lobar degenerationSarah Mizielinska1,2, Charlotte E. Ridler1, Rubika Balendra1,three, Annora Thoeng1, Nathan S. Woodling3, Friedrich A. Gr ser4, Vincent Plagnol5, Tammaryn Lashley6, Linda Partridge3,7 and Adrian M. Isaacs1*AbstractAn intronic GGGGCC expansion in C9orf72 is definitely the most typical 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 may localise for the nucleolus when expressed in cells, resulting in enlarged RANK L/TNFSF11 Protein medchemexpress nucleoli with disrupted functionality. In addition, GGGGCC repeat RNA can bind nucleolar proteins in vitro. Nonetheless, the relevance of nucleolar stress is unclear, as the arginine-rich DPR proteins don’t 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 method. Intriguingly, we identified that C9FTLD brain exhibited bidirectional nucleolar stress. C9FTLD neuronal nucleoli were significantly smaller sized than control neuronal nucleoli. On the other hand, inside C9FTLD brains, neurons containing poly(GR) inclusions had significantly bigger nucleolar volumes than neurons with out poly(GR) inclusions. Also, expression of poly(GR) in adult Drosophila neurons led to significantly enlarged nucleoli. A modest but significant improve 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 each DPR protein and repeat RNA toxicity. Key phrases: C9orf72, FTLD, Nucleolar pressure, Dipeptide repeat proteins, Poly(GR), RNA fociIntroduction An intronic GGGGCC expansion in C9orf72 would be the most typical identified cause of both frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) [7, 27]. Healthier folks have fewer than 30 repeats, whereas sufferers have a number of hundred to several thousand repeats [2, 7, 33]. The repeat expansion mutation may possibly lead to pathogenesis by loss of function from the C9orf72 protein, or gain-of-function mechanisms from i) sense and antisense repeat RNA and/or ii) the dipeptide repeat proteins poly(GA), poly(GP), poly(GR), poly(PR) and poly(AP), that are generated by repeat-associated non-ATG translation [28].* Correspondence: [email protected] Equal contributors 1 Division of Neurodegenerative Illness, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK Complete list of author details is offered in the finish on the articlePreviously, over-expression of poly(GR) and poly(PR) were reported to be very toxic to adult Drosophila neurons and key rat neurons [19, 34]. Overexpression of poly(GR) or poly(PR) repeats in cell models leads to their localisation in the nuc.
