The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-ΔNLS), and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-ΔNLS or hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions, corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-ΔNLS-expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-ΔNLS exhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.
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Cites
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Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
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TDP-43 Is a Developmentally Regulated Protein Essential for Early Embryonic Development
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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
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Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
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Self-citationPractical considerations for choosing a mouse model of Alzheimer’s disease
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TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets
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Metadata
- Authors
- Igaz, L. M., Kwong, L. K., Lee, E. B., Chen-Plotkin, A., Swanson, E., Unger, T., Malunda, J., Xu, Y., Winton, M. J., Trojanowski, J. Q., & Lee, V. M.-Y.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-02-01
- Volume
- 121
- Issue
- 2
- Pages
- 726-738
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2106000656
- Cited by
- 434
- References
- 11
- FWCI
- 25.06
- Type
- journal article
- Language
- en
- Open access
- green
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- Igaz, L. M., Kwong, L. K., Lee, E. B., Chen-Plotkin, A., Swanson, E., Unger, T., Malunda, J., Xu, Y., Winton, M. J., Trojanowski, J. Q., & Lee, V. M.-Y. (2011). Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. Journal of Clinical Investigation. https://doi.org/10.1172/jci44867
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