Seeded aggregation of ANXA11 induces prion-like propagation, TDP-43 co-pathology and nucleocytoplasmic transport defects

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. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/713853v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1aaad3org.highwire.dtl.DTLVardef@c51d5eorg.highwire.dtl.DTLVardef@10b2891org.highwire.dtl.DTLVardef@1945575_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIANXA11 undergoes liquid-liquid phase separation and matures into amyloid fibrils through a liquid-to-solid phase transition. C_LIO_LIANXA11 fibrils supports homotypic seeding and propagate within SH-SY5Y cells and iPSC-derived neurons. C_LIO_LIANXA11 fibrils induce TDP-43 pathological conversion, including phosphorylation and accumulation in insoluble aggregates. C_LIO_LIANXA11 aggregation is associated with nuclear pore complex remodeling, impaired mRNA export, and neuronal toxicity. C_LI In BriefANXA11 undergoes phase separation and matures into prion-like amyloid fibrils through a liquid-to-solid transition. These seeded assemblies propagate between cells and human neurons, induce TDP-43 pathological conversion, and are associated with remodeling of nuclear pore complexes, impaired mRNA export, and progressive neuronal toxicity. ANXA11 forms seeded amyloid assemblies that spread between cells, induce TDP-43 pathology, and disrupt nucleocytoplasmic transport.