Scholarlink

<p>The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation–ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO–ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月17日

查看全文
  • Kristina Wagner,
  • Jan Keiten-Schmitz,
  • Bikash Adhikari,
  • Upayan Patra,
  • Koraljka Husnjak,
  • François McNicoll,
  • Dorothee Dormann,
  • Michaela Müller-McNicoll,
  • Georg Tascher,
  • Elmar Wolf,
  • Stefan Müller

摘要

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation–ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO–ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.