Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease
- 1Johns Hopkins Medicine
Abstract
Dysfunction of TAR DNA-binding protein 43kDa (TDP-43) underlies amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with limited therapeutic options. While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A, the sufficiency of such a strategy to mitigate motor neuron disease remains unclear. Using a mouse model lacking TDP-43 in spinal motor neurons which mimics early stages of ALS, we show that the exclusion of Unc13a cryptic exon fails to mitigate motor neuron disease. In contrast, the restoration of multiple TDP-43 cryptic targets, including Unc13a, attenuated motor neuron loss, and rescued motor neuron disease. Additionally, compared to brain neurons, spinal motor neurons accumulate markedly lower amounts of Unc13a cryptic exons in mice and humans, suggesting that the contribution of this TDP-43 cryptic target to spinal motor neuron loss may be limited. Together, these results strongly support ALS therapeutic strategies designed to simultaneously restore multiple TDP-43 cryptic targets to attenuate spinal motor neuron loss.
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BibTeX
@misc{mallika2026restoring,
title = {{Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease}},
author = {A. Peethambaran Mallika and M. S. Baghel and O. Sitzman and J. Yu and T. Cao and S. Renganathan and I. Sinha and T. Melnikova and J. P. Ling and P. C. Wong},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.751082},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751082v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease
AU - A. Peethambaran Mallika
AU - M. S. Baghel
AU - O. Sitzman
AU - J. Yu
AU - T. Cao
AU - S. Renganathan
AU - I. Sinha
AU - T. Melnikova
AU - J. P. Ling
AU - P. C. Wong
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.751082
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.751082v1
AB - Dysfunction of TAR DNA-binding protein 43kDa (TDP-43) underlies amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with limited therapeutic options. While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A, the sufficiency of such a strategy to mitigate motor neuron disease remains unclear. Using a mouse model lacking TDP-43 in spinal motor neurons which mimics early stages of ALS, we show that the exclusion of Unc13a cryptic exon fails to mitigate motor neuron disease. In contrast, the restoration of multiple TDP-43 cryptic targets, including Unc13a, attenuated motor neuron loss, and rescued motor neuron disease. Additionally, compared to brain neurons, spinal motor neurons accumulate markedly lower amounts of Unc13a cryptic exons in mice and humans, suggesting that the contribution of this TDP-43 cryptic target to spinal motor neuron loss may be limited. Together, these results strongly support ALS therapeutic strategies designed to simultaneously restore multiple TDP-43 cryptic targets to attenuate spinal motor neuron loss.
ER -