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<p>Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons—cells that normally express only 3R-tau—induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.</p> Graphical abstract <p>Schematic representation of an embryonic mouse neuron illustrating key molecular changes described in this study. In the untreated state (upper part), the neuron expresses 3R-tau and tau mRNA lacking exon 10 (E10), with TDP-43 localized predominantly in the nucleus. Upon insulin stimulation (lower part), 4R-tau expression is induced along with tau mRNA including E10, and phosphorylated TDP-43 (pTDP-43) is redistributed toward the somatic compartment. CK1 is shown as the kinase responsible for TDP-43 phosphorylation, mediating the downstream events observed.</p>

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4R-tau isoform induction via TDP-43 in neurons in response to insulin: converging signaling pathways with implications for neurodegenerative disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Carina Weissmann,
  • Libia Catalina Salinas Castellanos,
  • Mayra Micaela Montes,
  • Gokhan Uruk,
  • Hossam Youssef,
  • R. Ross Reichard,
  • Rodolfo Gabriel Gatto,
  • Keith A Josephs

摘要

Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons—cells that normally express only 3R-tau—induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.

Graphical abstract

Schematic representation of an embryonic mouse neuron illustrating key molecular changes described in this study. In the untreated state (upper part), the neuron expresses 3R-tau and tau mRNA lacking exon 10 (E10), with TDP-43 localized predominantly in the nucleus. Upon insulin stimulation (lower part), 4R-tau expression is induced along with tau mRNA including E10, and phosphorylated TDP-43 (pTDP-43) is redistributed toward the somatic compartment. CK1 is shown as the kinase responsible for TDP-43 phosphorylation, mediating the downstream events observed.