Study on Annexin A11 Aggregation and TDP-43 Proteinopathies in Neurodegenerative Diseases

In this research report published in Acta Neuropathologica, researchers led by John L. Robinson from the University of Pennsylvania investigate the aggregation phenomena of Annexin A11 in neurodegenerative diseases, particularly in FTLD-TDP Type C, which is associated with frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP Type C). This research is set against the backdrop that TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein, is known to form inclusions in various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and FTLD-TDP. However, the associated Annexin A11 had not been thoroughly studied in cases of sporadic ALS and FTLD-TDP. The researchers aim to explore the relationship between TDP-43 and Annexin A11.

Research Background and Objectives

Background research indicates that TDP-43 protein mainly regulates splicing in the nucleus, but in the cytoplasm, it coexists with proteins like Annexin A11 in ribonucleoprotein (RNP) granules. Annexin A11 can anchor these ribonucleoprotein granules to lysosomes, facilitating their transport along axons or dendrites. While Annexin A11 aggregates have been reported in ALS and its variants, they had not been studied in sporadic ALS or FTLD-TDP cases. To gain a comprehensive understanding of the interplay between TDP-43 and Annexin A11 in neurodegenerative diseases, the research team decided to conduct this extensive analysis.

Research Sources

The primary authors of this paper include John L. Robinson, Eunran Suh, and Yan Xu, all from the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania Perelman School of Medicine. The study was received on April 16, 2024, revised on June 9, 2024, and accepted on June 10, 2024. The paper has been published online in the Acta Neuropathologica journal.

Research Process

Gene Analysis

The study analyzed the genetic data from 822 neurodegenerative disease autism cases to detect rare ANXA11 variants. Whole-genome sequencing and whole-exome sequencing were performed, and computational tools were used to screen for potential pathogenic variants.

Immunohistochemical Study

The research used immunohistochemical methods to analyze 368 autism cases to identify Annexin A11 aggregates. The immunohistochemical experiments involved screening various brain regions, including the motor cortex, spinal cord, and medial temporal lobe.

Protein Biochemical Analysis

Human post-mortem brain tissues were used for sequential protein extraction, followed by immunoblot analysis of soluble and insoluble proteins to confirm the relationship between Annexin A11 aggregation and TDP-43.

Research Results

Annexin A11 Aggregation in FTLD-TDP Type C

In 34 FTLD-TDP Type C cases screened, Annexin A11 aggregates were found in all cases, with morphology and regional distribution highly similar to TDP-43 inclusions. Dual immunofluorescence demonstrated a strong co-localization relationship between these two proteinopathies in most cases.

Findings in Other TDP-43 Proteinopathies

Annexin A11 aggregation was also found in a small number of other types of TDP-43 proteinopathies, including some ALS, FTLD-TDP Type A and Type B, and LATE-NC cases. Though less frequent in non-Type C cases, Annexin A11 aggregation still showed similar distribution and morphology to TDP-43 inclusions.

Special Cases

The study reported on two ANXA11 variants, including a known ALS-related p.G38R variant and a newly identified p.P75S variant. The p.G38R variant case showed co-localization of Annexin A11 with TDP-43 aggregates, while the p.P75S variant exhibited Annexin A11 aggregation independent of TDP-43, leading to severe striatum degeneration and vacuolation.

Biochemical Analysis Results

Biochemical analysis revealed the presence of insoluble full-length and truncated Annexin A11 proteins in FTLD-TDP Type C and ANXA11 variant cases, highlighting common characteristics of Annexin A11 and TDP-43 aggregates in these diseases.

Research Conclusion

The study demonstrates that Annexin A11 is a consistent pathological feature in FTLD-TDP Type C, and its aggregation was also found in some other TDP-43 proteinopathy cases. Significant findings suggest that Annexin A11 aggregation may be related to the upstream pathological mechanisms of TDP-43 proteinopathies. Additionally, the discovery of a new ANXA11 variant, p.P75S, supports the notion that Annexin A11 aggregation alone can induce neurodegeneration. This research provides valuable data and new directions for further exploration of the interaction between TDP-43 and Annexin A11 in neurodegenerative diseases.

Research Highlights

• Annexin A11 aggregates were found in all screened FTLD-TDP Type C cases, revealing a strong correlation with TDP-43 aggregates.
• Annexin A11 aggregation was identified in some other TDP-43 proteinopathy cases but was relatively rare, indicating that this protein may operate in specific pathological contexts.
• The discovery of the p.P75S variant suggests that Annexin A11 aggregation alone is sufficient to cause neurodegeneration, providing new insights into the mechanisms of neurodegenerative diseases.

Scientific and Practical Value of the Research

This study provides new insights into the pathological mechanisms of neurodegenerative diseases such as FTLD-TDP Type C, particularly highlighting the co-localization of Annexin A11 and TDP-43 aggregates. Furthermore, the identification of the p.P75S variant supports the independent role of Annexin A11 aggregation in neurodegeneration. The findings not only help elucidate the molecular mechanisms of these diseases but also provide essential data for future diagnosis and treatment.

Summary

Through detailed pathological and biochemical analysis, the research team successfully revealed the aggregation of Annexin A11 in various TDP-43 proteinopathies. This molecular-level study offers potentially valuable scientific data and provides critical guidance for future research and treatment strategies for neurodegenerative diseases.