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<p>Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca<sup>2+</sup> -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.</p>

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Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Yu Feng,
  • Tongshu Luan,
  • Zhenda Zhang,
  • Wei Wang,
  • Yuanyuan Chu,
  • Sijia Wan,
  • Xiaorong Pan,
  • Jie Li,
  • Yifan Liu,
  • Yaqian Xu,
  • Kun Dou,
  • Tong Wang

摘要

Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca2+ -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.