Luo, H.; Zheng, H.; Lu, Y.; Lu, C.; Zhang, K.; Duan, S.; Zhang, H.; Zhang, Y.; Song, Y.; Wang, T.; Liu, H.; Xia, Z.; Xu, Y.

Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the mechanisms linking ANXA11 dysfunction to neurodegeneration remain poorly defined. Recent cryo-EM studies revealed heteromeric ANXA11-TDP-43 filaments in patient brains, suggesting a direct pathological connection between these two ALS-associated proteins. However, whether ANXA11 possesses intrinsic amyloidogenic properties and how its aggregation relates to TDP-43 proteinopathy remain unknown. Here, we demonstrate that ANXA11 undergoes liquid-liquid phase separation and subsequently matures into amyloid fibrils through a liquid-to-solid phase transition. ANXA11 fibrils exhibit prion-like properties, including self-templating seeding activity and intercellular propagation in human iPSC-derived neurons. Strikingly, ANXA11 fibrils induces pathological conversion of TDP-43, including hyperphosphorylation, accumulation in detergent-insoluble fractions, and formation of cytoplasmic aggregates. TurboID proximity-labeling proteomics further revealed aggregation-dependent enrichment of nuclear pore complex and nucleocytoplasmic transport factors in the ANXA11 aggregate-proximal proteome. Consistently, ANXA11 aggregation was associated with nuclear envelope abnormalities, altered nucleoporin distribution, impaired mRNA export, and progressive neuronal toxicity in iPSC-derived neurons. Together, these findings establish ANXA11 as an intrinsically amyloidogenic, phase-transition-competent protein whose seeded assemblies propagate between cells, induce TDP-43 co-pathology, and are linked to nucleocytoplasmic transport defects and neuronal injury, thereby providing a mechanistic framework for ANXA11-associated ALS/FTD pathogenesis.