The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity
Open accessAbstract
Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. However, TDP-43 is not the only protein in disease-associated inclusions, and whether TDP-43 misfolds or is merely sequestered by other aggregated components is unclear. Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients [corrected] . The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro. Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
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TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
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Misfolded proteins partition between two distinct quality control compartments
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Prions as adaptive conduits of memory and inheritance
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Self-citationTDP ‐ 43 mutation in familial amyotrophic lateral sclerosis
Yokoseki, A., Shiga, A., Tan, C., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21392 · Cited by 373
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Cited by
Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis
Ling, S.-C., Polymenidou, M., & Cleveland, D. W. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.033 · Cited by 1,811
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration
Lagier-Tourenne, C., Polymenidou, M., & Cleveland, D. W. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq137 · Cited by 1,021
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS
Yu, C.-H., Davidson, S., Harapas, C. R., Hilton, J. B., Mlodzianoski, M. J., Laohamonthonkul, P., Louis, C., Low, R. R. J., Moecking, J., De Nardo, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.020 · Cited by 1,019
The changing scene of amyotrophic lateral sclerosis
Robberecht, W., & Philips, T. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3430 · Cited by 957
Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies
Ciechanover, A., & Kwon, Y. T. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.117 · Cited by 898
Metadata
- Authors
- Johnson, B. S., Snead, D., Lee, J. J., McCaffery, J. M., Shorter, J., & Gitler, A. D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 284
- Issue
- 30
- Pages
- 20329-20339
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2020159880
- Cited by
- 782
- References
- 9
- FWCI
- 23.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Johnson, B. S., Snead, D., Lee, J. J., McCaffery, J. M., Shorter, J., & Gitler, A. D. (2009). TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m109.010264
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