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Peer-reviewedCC BY-NC-ND 4.0Autophagy

RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis

  • Yujia Liu1,2
  • Guofang Xia3
  • Huaiying Shi1
  • Simeng Zhu3
  • Hailong Li1,2
  • Yifan Shi3
  • Wanling Ouyang3
  • Congfeng Xu3
  • Ailian Du1,2
  1. 1Department of Neurology, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
  2. 2Department of Neurology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  3. 3Department of Cardiology, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, Shanghai, China
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Abstract

Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Although CHRN internalization is well established in MG pathogenesis, the downstream cellular events, especially those related to autophagy, remain poorly described. Here, we report that RAPSN/rapsyn, an intracellular CHRN-binding protein essential for its clustering, accumulates as aggregates in experimental autoimmune myasthenia gravis (EAMG) mice. In CHRN antibody-treated myotubes, RAPSN dissociates from internalized CHRN and forms aggregates due to exposure of its hydrophobic domains. These aggregates in turn impair the trafficking and membrane incorporation of newly synthesized CHRN, thereby exacerbating CHRN loss. Notably, the accumulation of RAPSN aggregates facilitates formation of HSPA/HSP70-BAG3 complex, which recognizes and transports the aggregates along microtubules to form perinuclear aggresomes for subsequent lysosomal degradation. Accordingly, pharmacological inhibition or knockdown of HSPA-BAG3 complex increases RAPSN aggregation, which participates in enhanced CHRN loss and worsened muscle weakness in EAMG mice. This study identifies HSPA-BAG3 aggrephagy as a protective mechanism that clears RAPSN aggregates to maintain CHRN integrity and suggests a potential therapeutic strategy for MG.

Abbreviation: 3-MA: 3-methyladenine; AAV: adeno-associated virus; CASA: chaperone-assisted selective autophagy; CHRN/nicotinic acetylcholine receptor: cholinergic receptor nicotinic; CHRN-ab: CHRN antibodies; CHX: cycloheximide; CMAP: compound muscle action potential; CQ: chloroquine; EAMG: experimental autoimmune myasthenia gravis; ER: endoplasmic reticulum; GAS: gastrocnemius; MAP1LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MG: myasthenia gravis; NMJ: neuromuscular junction; Rapa: rapamycin; RAPSN/rapsyn: receptor associated protein of the synapse; SQSTM1: sequestosome 1; TA: tibialis anterior; αBTX-A594: α-bungarotoxin-Alexa-594.

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Cite

BibTeXRIS
BibTeX
@article{liu2026rapsnrapsyn,
  title = {{RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis}},
  author = {Yujia Liu and Guofang Xia and Huaiying Shi and Simeng Zhu and Hailong Li and Yifan Shi and Wanling Ouyang and Congfeng Xu and Ailian Du},
  journal = {Autophagy},
  year = {2026},
  month = jun,
  doi = {10.1080/15548627.2026.2693778},
  url = {https://doi.org/10.1080/15548627.2026.2693778},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis
AU  - Yujia Liu
AU  - Guofang Xia
AU  - Huaiying Shi
AU  - Simeng Zhu
AU  - Hailong Li
AU  - Yifan Shi
AU  - Wanling Ouyang
AU  - Congfeng Xu
AU  - Ailian Du
PY  - 2026
DA  - 2026/06/28
JO  - Autophagy
DO  - 10.1080/15548627.2026.2693778
UR  - https://doi.org/10.1080/15548627.2026.2693778
AB  - Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Although CHRN internalization is well established in MG pathogenesis, the downstream cellular events, especially those related to autophagy, remain poorly described. Here, we report that RAPSN/rapsyn, an intracellular CHRN-binding protein essential for its clustering, accumulates as aggregates in experimental autoimmune myasthenia gravis (EAMG) mice. In CHRN antibody-treated myotubes, RAPSN dissociates from internalized CHRN and forms aggregates due to exposure of its hydrophobic domains. These aggregates in turn impair the trafficking and membrane incorporation of newly synthesized CHRN, thereby exacerbating CHRN loss. Notably, the accumulation of RAPSN aggregates facilitates formation of HSPA/HSP70-BAG3 complex, which recognizes and transports the aggregates along microtubules to form perinuclear aggresomes for subsequent lysosomal degradation. Accordingly, pharmacological inhibition or knockdown of HSPA-BAG3 complex increases RAPSN aggregation, which participates in enhanced CHRN loss and worsened muscle weakness in EAMG mice. This study identifies HSPA-BAG3 aggrephagy as a protective mechanism that clears RAPSN aggregates to maintain CHRN integrity and suggests a potential therapeutic strategy for MG.  Abbreviation: 3-MA: 3-methyladenine; AAV: adeno-associated virus; CASA: chaperone-assisted selective autophagy; CHRN/nicotinic acetylcholine receptor: cholinergic receptor nicotinic; CHRN-ab: CHRN antibodies; CHX: cycloheximide; CMAP: compound muscle action potential; CQ: chloroquine; EAMG: experimental autoimmune myasthenia gravis; ER: endoplasmic reticulum; GAS: gastrocnemius; MAP1LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MG: myasthenia gravis; NMJ: neuromuscular junction; Rapa: rapamycin; RAPSN/rapsyn: receptor associated protein of the synapse; SQSTM1: sequestosome 1; TA: tibialis anterior; αBTX-A594: α-bungarotoxin-Alexa-594.
SN  - 1554-8627
SN  - 1554-8635
ER  -