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<p>Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of <i>KCNQ2</i>, which encodes a voltage-gated potassium channel (K<sub>v</sub>7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity of <i>KCNQ2</i> expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction.</p>

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TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Brian J. Joseph,
  • Kelly A. Marshall,
  • Peter Harley,
  • Jacob R. Mann,
  • Francesco Alessandrini,
  • Carlos G. Vanoye,
  • Wanhao Chi,
  • Mercedes Prudencio,
  • Dina Simkin,
  • Tzu-Ting Kao,
  • Reshma R. Desai,
  • Matthew J. Keuss,
  • Simone Barattucci,
  • Matteo Zanovello,
  • Puja R. Mehta,
  • Jean-Marc DeKeyser,
  • Francesco Limone,
  • Jonathan Lee,
  • Anna-Leigh Brown,
  • Marcel F. Leyton-Jaimes,
  • Leslie A. Nash,
  • Irune Guerra San Juan,
  • Eleonora Aronica,
  • Brian J. Wainger,
  • Mala Shah,
  • Anand Goswami,
  • Neil A. Shneider,
  • Dennis W. Dickson,
  • Juan Burrone,
  • Chaolin Zhang,
  • Hynek Wichterle,
  • Leonard Petrucelli,
  • Jonathan K. Watts,
  • Alfred L. George Jr,
  • Pietro Fratta,
  • Kevin Eggan,
  • Evangelos Kiskinis

摘要

Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of KCNQ2, which encodes a voltage-gated potassium channel (Kv7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity of KCNQ2 expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction.