Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43
7 affiliations
- 1Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA USA
- 2Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA USA
- 3Graduate Program in Neuroscience, University of Washington, Seattle, WA USA
- 4Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA USA
- 5Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA USA
- 6Department of Genome Sciences, Department of Medicine, University of Washington, Seattle, WA USA
- 7Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA USA
Abstract
While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 cause less neuronal dysfunction in C. elegans. Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.
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BibTeX
@article{long2026shared,
title = {{Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43}},
author = {Aaron Long and Heather N. Currey and Matvey Goldberg and Randall J. Eck and Marina Han and Rebecca L. Kow and Brian C. Kraemer and Nicole F. Liachko},
journal = {Cell Death \& Disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09143-9},
url = {https://doi.org/10.1038/s41419-026-09143-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43
AU - Aaron Long
AU - Heather N. Currey
AU - Matvey Goldberg
AU - Randall J. Eck
AU - Marina Han
AU - Rebecca L. Kow
AU - Brian C. Kraemer
AU - Nicole F. Liachko
PY - 2026
DA - 2026/08/11
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09143-9
UR - https://doi.org/10.1038/s41419-026-09143-9
AB - While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 cause less neuronal dysfunction in C. elegans. Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.
SN - 2041-4889
ER -