Aggregation and Cellular Toxicity of Pathogenic or Non-pathogenic Proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Biology

Background:

• Over 20 diseases, including diabetes, Alzheimer's, and Parkinson's, stem from pathogenic protein aggregation.
• Pathogenic proteins share toxicity upon aggregation despite diverse functions and structures.

Purpose of the Study:

• To investigate and compare the cellular toxicity of pathogenic and non-pathogenic protein aggregates.
• To characterize aggregation kinetics and toxicity over time under specific conditions.

Main Methods:

• Six proteins (three pathogenic, three non-pathogenic) were incubated at acid pH and high temperature.
• Aggregation kinetics and cellular toxicity were measured over time.
• Transmission Electron Microscopy (TEM) and Differential Scanning Calorimetry (DSC) were used for structural and thermal stability analysis.

Main Results:

• Non-pathogenic proteins (BSA, catalase, pepsin) were stable and non-toxic at 1 mg/mL but formed aggregates and induced transient toxicity at 20 mg/mL.
• Pathogenic proteins (lysozyme, SOD, insulin) formed aggregates and caused cytotoxicity at both 1 mg/mL and 20 mg/mL concentrations after 10 min.
• Pathogenic protein aggregates exhibited lower thermal stability (DSC) and induced toxicity, especially at 1 mg/mL, linked to fibrils.

Conclusions:

• Protein aggregate's cellular toxicity is influenced by its pathogenic nature and thermal stability.
• Low thermal stability in pathogenic protein aggregates is a key factor in their cytotoxicity.
• Findings enhance understanding of protein aggregation's role in disease pathogenesis.