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

Area of Science:

• Neuroimmunology
• Cellular Biology
• Autophagy

Background:

• Myasthenia gravis (MG) involves auto-antibodies targeting nicotinic acetylcholine receptors (CHRNs), leading to impaired neuromuscular junction (NMJ) transmission.
• While CHRN internalization is key in MG, downstream effects on cellular processes like autophagy are not well understood.

Purpose of the Study:

• To investigate the role of receptor-associated protein of the synapse (RAPSN) aggregation in experimental autoimmune myasthenia gravis (EAMG).
• To elucidate the cellular mechanisms, particularly autophagy, involved in clearing RAPSN aggregates and maintaining CHRN integrity.

Main Methods:

• Utilized experimental autoimmune myasthenia gravis (EAMG) mouse models and CHRN antibody-treated myotubes.
• Analyzed RAPSN aggregation, CHRN trafficking, and the involvement of the HSPA/HSP70-BAG3 complex in aggrephagy.

Main Results:

• RAPSN accumulates as aggregates in EAMG mice, impairing new CHRN membrane incorporation and worsening muscle weakness.
• The HSPA-BAG3 complex recognizes and transports RAPSN aggregates for lysosomal degradation via aggresomes.
• Inhibition of the HSPA-BAG3 complex exacerbates RAPSN aggregation and CHRN loss in EAMG.

Conclusions:

• HSPA-BAG3-mediated aggrephagy is a protective mechanism clearing RAPSN aggregates to preserve CHRN integrity.
• Targeting this aggrephagy pathway presents a potential therapeutic strategy for myasthenia gravis.