ALS Variants of Annexin A11’s Proline-Rich Domain Impair Its S100A6-Mediated Fibril Dissolution

• Published in: ACS chemical neuroscience 2023-08, Vol.14 (15), p.2583-2589
• Main Authors: Shihora, Aman, Elias, Ruben D., Hammond, John A., Ghirlando, Rodolfo, Deshmukh, Lalit
• Format: Article
• Language: English
• Subjects: Amyloid - metabolism; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Annexins - genetics; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; Humans; Letter; Neurodegenerative Diseases; Proline - genetics; S100 Calcium Binding Protein A6; Solubility
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.3c00169

Mutations in the proline-rich domain (PRD) of annexin A11 are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, and generate abundant neuronal A11 inclusions by an unknown mechanism. Here, we demonstrate that recombinant A11-PRD and its ALS-associated variants form liquidlike condensates that transform into β-sheet–rich amyloid fibrils. Surprisingly, these fibrils dissolved in the presence of S100A6, an A11 binding partner overexpressed in ALS. The ALS variants of A11-PRD showed longer fibrillization half-times and slower dissolution, even though their binding affinities for S100A6 were not significantly affected. These findings indicate a slower fibril-to-monomer exchange for these ALS variants, resulting in a decreased level of S100A6-mediated fibril dissolution. These ALS-A11 variants are thus more likely to remain aggregated despite their slower fibrillization.