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Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration.

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.
PMID
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Authors

Mayor MeshTerms
Keywords

C9orf72

Dipeptide repeat proteins

FTLD

Nucleolar stress

Poly(GR)

RNA foci

Journal Title acta neuropathologica communications
Publication Year Start




PMID- 28420437
OWN - NLM
STAT- MEDLINE
DA  - 20170419
DCOM- 20170420
LR  - 20170421
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 5
IP  - 1
DP  - 2017 Apr 18
TI  - Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration.
PG  - 29
LID - 10.1186/s40478-017-0432-x [doi]
AB  - 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.
FAU - Mizielinska, Sarah
AU  - Mizielinska S
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
      Square, London, WC1N 3BG, UK.
AD  - Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of
      Psychiatry, Psychology and Neuroscience, London, SE5 9RT, UK.
FAU - Ridler, Charlotte E
AU  - Ridler CE
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
      Square, London, WC1N 3BG, UK.
FAU - Balendra, Rubika
AU  - Balendra R
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
      Square, London, WC1N 3BG, UK.
AD  - Department of Genetics, Evolution and Environment, Institute of Healthy Ageing,
      University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
FAU - Thoeng, Annora
AU  - Thoeng A
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
      Square, London, WC1N 3BG, UK.
FAU - Woodling, Nathan S
AU  - Woodling NS
AD  - Department of Genetics, Evolution and Environment, Institute of Healthy Ageing,
      University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
FAU - Grasser, Friedrich A
AU  - Grasser FA
AD  - Institute of Virology, Saarland University Medical School, 66421, Hamburg,
      Germany.
FAU - Plagnol, Vincent
AU  - Plagnol V
AD  - UCL Genetics Institute, University College London, London, WC1E 6BT, UK.
FAU - Lashley, Tammaryn
AU  - Lashley T
AD  - Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of
      Neurology, Queen Square, London, WC1N 3BG, UK.
FAU - Partridge, Linda
AU  - Partridge L
AD  - Department of Genetics, Evolution and Environment, Institute of Healthy Ageing,
      University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
AD  - Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931,
      Cologne, Germany.
FAU - Isaacs, Adrian M
AU  - Isaacs AM
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
      Square, London, WC1N 3BG, UK. [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170418
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
RN  - 0 (C9orf72 protein, human)
RN  - 0 (Proteins)
SB  - IM
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Cell Nucleolus/*metabolism/*pathology
MH  - Cell Nucleus Size/genetics/physiology
MH  - DNA Repeat Expansion
MH  - Drosophila
MH  - Fluorescent Antibody Technique
MH  - Frontal Lobe/metabolism/pathology
MH  - Frontotemporal Lobar Degeneration/genetics/*metabolism/*pathology
MH  - Humans
MH  - Imaging, Three-Dimensional
MH  - In Situ Hybridization, Fluorescence
MH  - Intranuclear Inclusion Bodies/metabolism/pathology
MH  - Microscopy, Confocal
MH  - Neurons/metabolism/pathology
MH  - Proteins/genetics/*metabolism
MH  - Stress, Physiological/genetics/physiology
PMC - PMC5395972
OTO - NOTNLM
OT  - C9orf72
OT  - Dipeptide repeat proteins
OT  - FTLD
OT  - Nucleolar stress
OT  - Poly(GR)
OT  - RNA foci
EDAT- 2017/04/20 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/20 06:00
PHST- 2017/04/05 [received]
PHST- 2017/04/06 [accepted]
AID - 10.1186/s40478-017-0432-x [doi]
AID - 10.1186/s40478-017-0432-x [pii]
PST - epublish
SO  - Acta Neuropathol Commun. 2017 Apr 18;5(1):29. doi: 10.1186/s40478-017-0432-x.

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