The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death
Open accessAbstract
SUMMARY Expanded GGGGCC nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granules formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human-induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.
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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
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The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
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C9orf72 nucleotide repeat structures initiate molecular cascades of disease
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RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
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GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport
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C9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons
Shi, Y., Lin, S., Staats, K. A., Li, Y., Chang, W.-H., Hung, S.-T., Hendricks, E., Linares, G. R., Wang, Y., Son, E. Y., et al. (2018) · Nature Medicine · doi:10.1038/nm.4490 · Cited by 566
Self-citation
Metadata
- Authors
- Wen, X., Tan, W., Westergard, T., Krishnamurthy, K., Markandaiah, S. S., Shi, Y., Lin, S., Shneider, N. A., Monaghan, J., Pandey, U. B., Pasinelli, P., Ichida, J. K., & Trotti, D.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 84
- Issue
- 6
- Pages
- 1213-1225
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2088483634
- Cited by
- 527
- References
- 45
- FWCI
- 24.64
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Wen, X., Tan, W., Westergard, T., Krishnamurthy, K., Markandaiah, S. S., Shi, Y., Lin, S., Shneider, N. A., Monaghan, J., Pandey, U. B., Pasinelli, P., Ichida, J. K., & Trotti, D. (2014). Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death. Neuron. https://doi.org/10.1016/j.neuron.2014.12.010
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