| Details: |
The formation of protein deposits in human tissues is a defining feature of more than fifty disorders, including Alzheimer’s disease, Parkinson’s Disease, Type II diabetes, cardiovascular diseases, and a certain subgroup of cancer. Strong genetic and histological evidence links these devastating conditions to the process of protein misfolding and aggregation. Yet, it has remained challenging to identify a definitive connection between protein aggregation and pathogenicity. In this context, using single-molecule and super-resolution imaging, we develop a high-throughput assay based on quantifying the extent of toxic aggregate-induced membrane damage of individual nanosized lipid vesicles. Our results indicate a specific role of protein aggregate formation during the aggregation process in driving deleterious biological function and establishing a direct causative connection between amyloid aggregate formation and its pathological effects. Moreover, using this method, we can detect toxic protein aggregates in complex human bio-fluids, such as cerebrospinal fluid and serum, and thus has broad applicability in developing protein-based biomarkers for early accurate diagnosis. |