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Background <p>Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.</p> Methods <p>To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.</p> Results <p>We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in <i>C. elegans</i>.</p> Conclusions <p>We present an optogenetic <i>C. elegans</i> model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.</p>

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Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Kyung Hwan Park,
  • Euihyeon Yu,
  • Sooji Choi,
  • Sangyeong Kim,
  • Chanbin Park,
  • J. Eugene Lee,
  • Kyung Won Kim

摘要

Background

Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.

Methods

To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.

Results

We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans.

Conclusions

We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.