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The C-Terminal TDP-43 Fragments Have a High Aggregation Propensity and Harm Neurons by a Dominant-Negative Mechanism
Open accessAbstract
TAR DNA binding protein 43 KD (TDP-43) is an essential gene that regulates gene transcription, mRNA splicing and stability. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal neurodegenerative diseases, TDP-43 is fragmented, generating multiple fragments that include the C-terminal fragment of ∼25 KD. The role of these fragments in the pathogenesis of ALS and FTD is not clear. Here we investigated the aggregation propensity in various polypeptide regions of TDP-43 in mammalian cells and the effect of these fragments on cultured neurons. By expressing the full length and various TDP-43 fragments in motor neuron-derived NSC-34 cells and primary neurons, we found that both N- and C-terminal fragments of TDP-43 are prone to aggregate and the C-terminal end of RRM2 region is required, though not sufficient, for aggregation. The aggregation of the TDP-43 fragments can drive co-aggregation with the full-length TDP-43, consequently reducing the nuclear TDP-43. In addition, the TDP-43 fragments can impair neurite growth during neuronal differentiation. Importantly, overexpression of the full-length TDP-43 rescues the neurite growth phenotype whereas knockdown of the endogenous TDP-43 reproduces this phenotype. These results suggest that TDP-43 fragments, particularly the pathologically relevant C-terminal fragments, can impair neuronal differentiation by dominant-negatively interfering with the function of the full length TDP-43, thus playing a role in pathogenesis in ALS and FTD.
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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
The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity
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TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Velde, C. V., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., et al. (2008) · Nature Genetics · doi:10.1038/ng.132 · Cited by 1,544
Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., Beach, T. G., Buratti, E., Baralle, F., Morita, M., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21425 · Cited by 777
TDP-43 Is a Developmentally Regulated Protein Essential for Early Embryonic Development
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Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis
Kraemer, B. C., Schuck, T., Wheeler, J. M., Robinson, L. C., Trojanowski, J. Q., Lee, V. M. Y., & Schellenberg, G. D. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0659-0 · Cited by 350
Cited by
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00025 · Cited by 774
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
Lee, E. B., Lee, V. M.-Y., & Trojanowski, J. Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3121 · Cited by 659
Protein aggregation in amyotrophic lateral sclerosis
Blokhuis, A. M., Groen, E. J. N., Koppers, M., van den Berg, L. H., & Pasterkamp, R. J. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1125-6 · Cited by 579
Extracellular vesicles in neurodegenerative disease — pathogenesis to biomarkers
Thompson, A. G., Gray, E., Heman-Ackah, S. M., Mäger, I., Talbot, K., Andaloussi, S. E., Wood, M. J., & Turner, M. R. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.68 · Cited by 431
The role of liquid–liquid phase separation in aggregation of the TDP-43 low-complexity domain
Babinchak, W. M., Haider, R., Dumm, B. K., Sarkar, P., Surewicz, K., Choi, J.-K., & Surewicz, W. K. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007222 · Cited by 396
Metadata
- Authors
- Yang, C., Tan, W., Whittle, C., Qiu, L., Cao, L., Akbarian, S., & Xu, Z.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-12-31
- Volume
- 5
- Issue
- 12
- Pages
- e15878
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W1994982825
- Cited by
- 189
- References
- 6
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- gold
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- Yang, C., Tan, W., Whittle, C., Qiu, L., Cao, L., Akbarian, S., & Xu, Z. (2010). The C-Terminal TDP-43 Fragments Have a High Aggregation Propensity and Harm Neurons by a Dominant-Negative Mechanism. PLoS ONE. https://doi.org/10.1371/journal.pone.0015878
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