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C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins
- Source :
- Nature reviews / Neuroscience 19(5), 668-677 (2016). doi:10.1038/nn.4272, Nature neuroscience, vol 19, iss 5, Nature neuroscience
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- Neuronal inclusions of poly(GA), a protein unconventionally translated from G(4)C(2) repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
- Subjects :
- 0301 basic medicine
metabolism [Inclusion Bodies]
Gene Expression
Neurodegenerative
Inclusion bodies
Mice
genetics [Gene Expression]
0302 clinical medicine
pathology [Brain]
C9orf72
Gene expression
Psychology
pathology [Neurons]
Guanine Nucleotide Exchange Factors
ultrastructure [Inclusion Bodies]
Neurons
Inclusion Bodies
C9orf72 protein, mouse
pathology [Atrophy]
Behavior, Animal
General Neuroscience
Nucleocytoplasmic Transport Proteins
Neurodegeneration
Brain
pathology [Nerve Degeneration]
metabolism [Proteins]
Ubiquitinated Proteins
DNA-Binding Proteins
poly(glycyl-alanyl)
Xpc protein, mouse
metabolism [Neurons]
Frontotemporal Dementia
metabolism [Frontotemporal Dementia]
Cognitive Sciences
Rad23a protein, mouse
metabolism [DNA-Binding Proteins]
metabolism [Ubiquitinated Proteins]
metabolism [Guanine Nucleotide Exchange Factors]
Primary Cell Culture
Biology
Rad23b protein, mouse
DNA-binding protein
Article
03 medical and health sciences
TDP-43 protein, mouse
ddc:570
Acquired Cognitive Impairment
medicine
Animals
Humans
pathology [Amyotrophic Lateral Sclerosis]
Behavior
Neurology & Neurosurgery
C9orf72 Protein
toxicity [Proteins]
Animal
metabolism [Amyotrophic Lateral Sclerosis]
Amyotrophic Lateral Sclerosis
Neurosciences
Proteins
medicine.disease
genetics [Proteins]
Brain Disorders
030104 developmental biology
metabolism [Brain]
Nucleocytoplasmic Transport
Nerve Degeneration
pathology [Frontotemporal Dementia]
Mutation
ultrastructure [Brain]
Dementia
Human medicine
Atrophy
Carrier Proteins
Neuroscience
030217 neurology & neurosurgery
metabolism [Carrier Proteins]
Subjects
Details
- ISSN :
- 15461726 and 10976256
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Nature Neuroscience
- Accession number :
- edsair.doi.dedup.....64c82cd0d13a2f06a3feaadec00965c0