Human iPSC-derived motor neurons with TDP-43 nuclear loss present early ALS pathological phenotypes

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive loss of motor neurons and presents a critical need for effective treatments. To investigate the impact of TAR DNA-binding protein 43 (TDP-43) nuclear depletion in ALS, we established and characterized a human-induced pluripotent stem cell-derived motor neuron model carrying a mutation that disrupts TDP-43 nuclear localization. The model successfully recapitulates functional deficits observed in ALS patients, including impaired neurite outgrowth, reduced axonal regeneration, and neuronal hyperexcitability. Proteomic and metabolomic profiling revealed early mechanisms underlying ALS neuronal pathophysiology, involving altered oxidative stress and neurotransmitter release. TDP-43 nuclear depletion led to mis-splicing STMN2 and KCNQ2 , defects characteristic of TDP-43-associated disease. Notably, a splice-switching antisense oligonucleotide successfully restored normal STMN2 splicing and function, demonstrating that directly correcting splicing defects can rescue motor neurons. This work provides a comprehensive understanding of TDP-43 nuclear depletion in the context of ALS pathogenesis and offers potential targets for RNA-targeted therapeutic intervention, pointing towards the development of precision medicine approaches and early diagnostic markers for ALS.

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Cite

BibTeX RIS

BibTeX

@article{chan2026human,
  title = {{Human iPSC-derived motor neurons with TDP-43 nuclear loss present early ALS pathological phenotypes}},
  author = {Tze Khee Chan and Shahriar Niroomand and U-Ming Lim and Emelyne Teo and Nikhil Kumar Tulsian and Tayfun Tumkaya and Craig A. Parish and Vladimir Simov and Jia Ling Tiffany Yeo and Jing Wesley Leong and Bhavya Voleti and Michael J. Marino and Rebecca M. Klein and Delphine Fagegaltier and Aaron Zefrin Fernandis},
  journal = {Communications Biology},
  year = {2026},
  month = oct,
  doi = {10.1038/s42003-026-10832-6},
  url = {https://www.nature.com/articles/s42003-026-10832-6},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Human iPSC-derived motor neurons with TDP-43 nuclear loss present early ALS pathological phenotypes
AU  - Tze Khee Chan
AU  - Shahriar Niroomand
AU  - U-Ming Lim
AU  - Emelyne Teo
AU  - Nikhil Kumar Tulsian
AU  - Tayfun Tumkaya
AU  - Craig A. Parish
AU  - Vladimir Simov
AU  - Jia Ling Tiffany Yeo
AU  - Jing Wesley Leong
AU  - Bhavya Voleti
AU  - Michael J. Marino
AU  - Rebecca M. Klein
AU  - Delphine Fagegaltier
AU  - Aaron Zefrin Fernandis
PY  - 2026
DA  - 2026/10/10
JO  - Communications Biology
DO  - 10.1038/s42003-026-10832-6
UR  - https://www.nature.com/articles/s42003-026-10832-6
AB  - Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive loss of motor neurons and presents a critical need for effective treatments. To investigate the impact of TAR DNA-binding protein 43 (TDP-43) nuclear depletion in ALS, we established and characterized a human-induced pluripotent stem cell-derived motor neuron model carrying a mutation that disrupts TDP-43 nuclear localization. The model successfully recapitulates functional deficits observed in ALS patients, including impaired neurite outgrowth, reduced axonal regeneration, and neuronal hyperexcitability. Proteomic and metabolomic profiling revealed early mechanisms underlying ALS neuronal pathophysiology, involving altered oxidative stress and neurotransmitter release. TDP-43 nuclear depletion led to mis-splicing STMN2 and KCNQ2 , defects characteristic of TDP-43-associated disease. Notably, a splice-switching antisense oligonucleotide successfully restored normal STMN2 splicing and function, demonstrating that directly correcting splicing defects can rescue motor neurons. This work provides a comprehensive understanding of TDP-43 nuclear depletion in the context of ALS pathogenesis and offers potential targets for RNA-targeted therapeutic intervention, pointing towards the development of precision medicine approaches and early diagnostic markers for ALS.
SN  - 2399-3642
ER  -

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