Physiological and pathological roles of ANXA11: a multifunctional regulator in neurodegeneration and other disorders

Annexin A11 (ANXA11) is a Ca²⁺-dependent phospholipid-binding protein of the annexin family, which has been traditionally studied for its established roles in tumor progression and autoimmune disorders. Recent studies have highlighted the roles of ANXA11 in newly discovered mechanisms related to neurodegenerative diseases, including liquid-liquid phase separation (LLPS), membrane lipid coupling, and function as a molecular tether linking membraneless organelles to lysosomal membranes. Recent landmark findings reveal that ANXA11 co-assembles with TAR DNA-binding protein 43(TDP-43) into heteromeric amyloid filaments, suggesting that these pathological amyloid structures may play a crucial role in neurodegeneration. In this review, we comprehensively explored the physiological and pathological roles of ANXA11 in neurodegeneration and other disorders, with a focus on LLPS, membrane dynamics, and amyloidogenesis. We discussed potential therapeutic strategies targeting the unique properties of ANXA11 and proposed several critical scientific questions that need to be explored.