2025/05/26 by Khushboo Rani, Bharat Gurnani, Neha Jain · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · Materials Science · #Alzheimer's disease research and treatments #Protein Structure and Dynamics #Supramolecular Self-Assembly in Materials
paper · doi:10.1111/febs.70142
openalex publication_date 2025/05/26 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/27
Self‐assembly of proteins and peptides into amyloid fibrils is an active field of research due to its connection with debilitating human ailments such as Parkinson's disease, dialysis‐related amyloidosis (DRA), and type II diabetes. In most disease conditions, amyloid formation proceeds via distinct on‐pathway conformers such as oligomers and protofibrils. However, the detailed mechanism by which monomers transform into different species and contribute to disease progression remains an area of intense research. Isolating and characterizing distinct conformers are pertinent to understanding disease initiation and progression. One such ailment is DRA, where an amyloidogenic protein, β 2 ‐microglobulin (β 2 m), undergoes a profound conformational switch to adopt an amyloid fold. β 2 m amyloids accumulate in tissues such as joints and kidneys, causing tissue damage and dysfunction. Soluble β 2 m oligomers are considered more toxic than amyloids due to impaired cellular processes, resulting in cell death. In the present study, we have identified and characterized three stages of β 2 m aggregation, namely, oligomers, protofibrils, and fibrils, while varying salt concentrations and agitation under low pH conditions. Our kinetic results indicate that β 2 m oligomers and protofibrils follow a nucleation‐independent pathway, whereas amyloids are formed through the classical nucleation process. Further, we implemented microscopic techniques and biochemical assays to verify the formation and stability of distinct conformers. We believe these findings provide insights into the process of amyloid formation, which may help us to understand the initiation of the disease at an early stage.