ArticleProceedings of the National Academy of Sciences of the United States of America2017
Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 71 citations in OpenAlex.
- Surface cues shape procoagulant properties of amyloidogenic microclots.Cell death & disease · 2026Review
- Mapping the hippocampal spatial proteomic signature in male and female mice of an early Alzheimer's disease model.Biology of sex differences · 2025Article
- Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.Journal of molecular biology · 2025Article
- Podoplanin-positive cell-derived small extracellular vesicles contribute to cardiac amyloidosis after myocardial infarction.Cell reports · 2025Article
- Acquired Renal Amyloidosis in a Patient With X-Linked Hyper-IgM Immunodeficiency With Novel Hemizygotic Pathogenic Variant in CD40LG Gene.Case reports in nephrology · 2025Article
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
- A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome.International journal of molecular sciences · 2024Article
- Article
- 27-hydroxycholesterol causes cognitive deficits by disturbing Th17/Treg balance and the related immune responses in mild cognitive impairment patients and C57BL/6J mice.Journal of neuroinflammation · 2023Article
- On-Pathway Oligomer of Human Islet Amyloid Polypeptide Induced and Stabilized by Mechanical Rotation during Magic Angle Spinning Nuclear Magnetic Resonance.The journal of physical chemistry letters · 2023Article
- On-Pathway Oligomer of Human Islet Amyloid Polypeptide Induced and Stabilized by Mechanical Rotation During MAS NMR.bioRxiv : the preprint server for biology · 2023Article
- The Apparent Organ-Specificity of Amyloidogenic ApoA-I Variants Is Linked to Tissue-Specific Extracellular Matrix Components.International journal of molecular sciences · 2022Article
- Cryo-EM structure of ex vivo fibrils associated with extreme AA amyloidosis prevalence in a cat shelter.Nature communications · 2022Article
- Regulation of Th17/Treg Balance by 27-Hydroxycholesterol and 24S-Hydroxycholesterol Correlates with Learning and Memory Ability in Mice.International journal of molecular sciences · 2022Article
- Autophagy Alteration in ApoA-I Related Systemic Amyloidosis.International journal of molecular sciences · 2022Article
- Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.Biophysical chemistry · 2022Review
- Understanding AL amyloidosis with a little help fromFrontiers in immunology · 2022Review
- Adaptation of Microarray Assay for Serum Amyloid a Analysis in Human Serum.Molecular biology · 2022Article
- Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice.International journal of molecular sciences · 2021Article
- Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment.Molecules (Basel, Switzerland) · 2021Review
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5-4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5-4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.
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