TDP43 Autoregulation Gives Rise to Dominant Negative Isoforms That are Tightly Controlled by Transcriptional and Post-translational Mechanisms

Authors

Megan M. Dykstra, University of Michigan, Ann Arbor
Kaitlin Weskamp, Nebraska Wesleyan University
Nicolás B. Gómez, University of Michigan, Ann Arbor
Jacob Waksmacki, University of Michigan, Ann Arbor
Elizabeth Tank, University of Michigan, Ann Arbor
M. Rebecca Glineburg, Chapman UniversityFollow
Allison Snyder, NINDS, NIH
Emile Pinarbasi, University of Michigan, Ann Arbor
Michael Bekier, University of Michigan, Ann Arbor
Xingli Li, University of Michigan, Ann Arbor
Morgan R. Miller, University of Michigan, Ann Arbor
Jen Bai, University of Michigan, Ann Arbor
Shameena Shahzad, University of Michigan, Ann Arbor
Neha Nedumaran, University of Michigan, Ann Arbor
Clare Wieland, University of Michigan, Ann Arbor
Corey Stewart, University of Michigan, Ann Arbor
Sydney Willey, University of Michigan, Ann Arbor
Nikolas Grotewold, University of Michigan, Ann Arbor
Jonathon McBride, University of Michigan, Ann Arbor
John J. Moran, Emory University
Aditya V. Suryakumar, University of Michigan, Ann Arbor
Michael Lucas, University of Michigan, Ann Arbor
Peter M. Tessier, University of Michigan, Ann Arbor
Michael Ward, NINDS, NIH
Peter K. Todd, University of Michigan, Ann Arbor
Sami J. Barmada, University of Michigan, Ann Arbor

Document Type

Article

Publication Date

1-9-2025

Abstract

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.

Comments

This article was originally published in Cell Reports, volume 44, issue 1, in 2025. https://doi.org/10.1016/j.celrep.2024.115113

Recommended Citation

Dykstra, M.M., Weskamp, K., Gómez, N.B., Waksmacki, J., Tank, E., Glineburg, M.R., Snyder, A., Pinarbasi, E., Bekier, M., Li, X., et al. (2025). TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms. Cell Reports 44, 115113. https://doi.org/10.1016/j.celrep.2024.115113

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.