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<p>In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in <i>Drosophila</i> ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion.</p>

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TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins

  • 期刊论文

  • 发表日期：

    2025年10月31日

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  • Shan Lu,
  • Sitao Zhang,
  • Spencer Oung,
  • Jolene K. Diedrich,
  • Peng Han,
  • Olatz Arnold-Garcia,
  • Takuya Ohkubo,
  • Olubankole Aladesuyi Arogundade,
  • Sonia Vazquez-Sanchez,
  • Ke Zhang,
  • John Ravits,
  • John R. Yates III,
  • Don W. Cleveland

摘要

In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion.