Annexin A11 (ANXA11) is a gene encoding a Ca2+-dependent phospholipid-binding protein. It is involved in multiple cellular functions, such as intracellular Ca2+ homeostasis, and it acts as a molecular tether between RNA granules and lysosomes for long-distance RNA transport. ANXA11 also plays a role in protein-lipid phase coupling on lysosomal membranes, with its N-terminus driving phase state changes in proteins and underlying membrane lipids.

Mutations in ANXA11 have been associated with various neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), ANXA11 mutations dysregulate calcium homeostasis and stress granule dynamics. In corticobasal syndrome, the P93S variant in ANXA11 leads to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43, along with cryptic exon expression. Moreover, ANXA11 mutations can cause aggregation, altered lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization, presenting as ALS or frontotemporal dementia. In FTLD-TDP type C, ANXA11 co-assembles with TDP-43 in heteromeric amyloid filaments, redefining the histopathology of this disease.

In conclusion, ANXA11 is essential for maintaining normal cellular functions, especially in processes related to RNA transport, calcium homeostasis, and protein-lipid interactions. Research on ANXA11 mutations in various disease models, mainly in neurodegenerative diseases like ALS, frontotemporal dementia, and corticobasal syndrome, has deepened our understanding of the disease mechanisms. These studies provide potential targets for future therapeutic strategies against these neurodegenerative disorders.

References:

1. Snyder, Allison, Ryan, Veronica H, Hawrot, James, Cookson, Mark R, Ward, Michael E. 2024. An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 20, 5220-5235. doi:10.1002/alz.13915. https://pubmed.ncbi.nlm.nih.gov/38923692/

2. Snyder, Allison, Ryan, Veronica H, Hawrot, James, Cookson, Mark R, Ward, Michael E. 2023. An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome. In Research square, , . doi:10.21203/rs.3.rs-3462973/v1. https://pubmed.ncbi.nlm.nih.gov/37886540/

3. Arseni, Diana, Nonaka, Takashi, Jacobsen, Max H, Hasegawa, Masato, Ryskeldi-Falcon, Benjamin. 2024. Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C. In Nature, 634, 662-668. doi:10.1038/s41586-024-08024-5. https://pubmed.ncbi.nlm.nih.gov/39260416/

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5. Wang, Yu, Duan, Xiaohui, Zhou, Xiao, Sun, Yu, Peng, Dantao. 2022. ANXA11 mutations are associated with amyotrophic lateral sclerosis-frontotemporal dementia. In Frontiers in neurology, 13, 886887. doi:10.3389/fneur.2022.886887. https://pubmed.ncbi.nlm.nih.gov/36226077/

6. Nixon-Abell, Jonathon, Ruggeri, Francesco S, Qamar, Seema, Knowles, Tuomas P J, St George-Hyslop, Peter. 2023. ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.03.22.533832. https://pubmed.ncbi.nlm.nih.gov/36993242/

7. Liao, Ya-Cheng, Fernandopulle, Michael S, Wang, Guozhen, Lippincott-Schwartz, Jennifer, Ward, Michael E. . RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether. In Cell, 179, 147-164.e20. doi:10.1016/j.cell.2019.08.050. https://pubmed.ncbi.nlm.nih.gov/31539493/