TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms

Megan M Dykstra; Kaitlin Weskamp; Nicolás B Gómez; Jacob Waksmacki; Elizabeth Tank; M Rebecca Glineburg; Allison Snyder; Emile Pinarbasi; Michael Bekier; Xingli Li; Morgan R Miller; Jen Bai; Shameena Shahzad; Neha Nedumaran; Clare Wieland; Corey Stewart; Sydney Willey; Nikolas Grotewold; Jonathon McBride; John J Moran; Aditya V Suryakumar; Michael Lucas; Peter M Tessier; Michael Ward; Peter K Todd; Sami J Barmada

doi:10.1016/j.celrep.2024.115113

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms

Cell Rep. 2025 Jan 28;44(1):115113. doi: 10.1016/j.celrep.2024.115113. Epub 2025 Jan 9.

Authors

Megan M Dykstra¹, Kaitlin Weskamp², Nicolás B Gómez³, Jacob Waksmacki⁴, Elizabeth Tank⁴, M Rebecca Glineburg⁵, Allison Snyder⁶, Emile Pinarbasi⁷, Michael Bekier⁴, Xingli Li⁴, Morgan R Miller¹, Jen Bai⁴, Shameena Shahzad⁴, Neha Nedumaran⁴, Clare Wieland⁸, Corey Stewart¹, Sydney Willey¹, Nikolas Grotewold⁹, Jonathon McBride¹⁰, John J Moran¹¹, Aditya V Suryakumar⁴, Michael Lucas¹², Peter M Tessier¹², Michael Ward⁶, Peter K Todd¹³, Sami J Barmada¹⁴

Affiliations

¹ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
² Chemistry Department, Nebraska Wesleyan University, Lincoln, NE, USA.
³ Graduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
⁵ Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA, USA.
⁶ Neurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.
⁷ Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Neuropathology, Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
⁸ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
⁹ Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
¹¹ Atlanta Pediatric Research Alliance, Emory University, Atlanta, GA, USA.
¹² Departments of Chemical Engineering and Pharmaceutical Sciences, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
¹³ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Veterans Affairs Medical Center, Ann Arbor, MI, USA.
¹⁴ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: sbarmada@umich.edu.

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.

Keywords: ALS; CP: Molecular biology; CP: Neuroscience; FTLD-TDP; TDP43; cryptic splicing; neurodegeneration; nonsense-mediated RNA decay.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
HEK293 Cells
Homeostasis*
Humans
Mice
Nonsense Mediated mRNA Decay
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Processing, Post-Translational*
Transcription, Genetic*

Substances

Protein Isoforms
DNA-Binding Proteins
TARDBP protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding