Co-aggregation of annexin A11 and TDP-43 in FTLD/MND with primary lateral sclerosis phenotype

TL;DR

This study explores how annexin A11 and TDP-43 proteins co-aggregate in a specific type of neurodegenerative disease, potentially helping distinguish between different disease subtypes.

Contribution

The study identifies co-aggregation of annexin A11 and TDP-43 in PLS-TDP cases, offering a new neuropathological marker for distinguishing PLS from ALS.

Findings

ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP cases.

PLS-TDP cases show distinct TDP-43 fragment patterns compared to other FTLD-TDP subtypes.

TDP-43 and ANXA11 heteromeric filaments are present in PLS-TDP cases.

Abstract

TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.

The online version contains supplementary material available at 10.1186/s40478-025-02210-w.

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