Big versus small: The impact of aggregate size in disease

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Protein aggregation, forming soluble oligomers and insoluble fibrils, is implicated in neurodegenerative diseases.
• Historically, insoluble fibrils were considered the primary cause of neuronal death, but soluble oligomers are now recognized as toxic species.
• Current therapeutic strategies often group all aggregates or focus solely on fibrils, potentially overlooking the distinct roles of oligomers.

Approach:

• Reviewing the role of different-sized protein aggregates (oligomers vs. fibrils) in disease pathogenesis.
• Examining factors influencing aggregation pathways, such as mutations, metal ions, post-translational modifications, and lipid interactions.
• Analyzing computational modeling strategies, including molecular dynamics and kinetic modeling, for simulating both oligomers and fibrils.
• Outlining current therapeutic approaches targeting protein aggregation, evaluating their efficacy against oligomers versus fibrils.

Key Points:

• Soluble oligomers and insoluble fibrils represent distinct species with different roles in neurodegenerative disease.
• Factors like mutations and lipid interactions can influence the propensity for protein aggregation towards oligomers or fibrils.
• Computational models are essential tools for understanding the structural and dynamic properties of both oligomers and fibrils.
• Therapeutic strategies must differentiate between aggregate species to effectively target the toxic entities.

Conclusions:

• Accurate identification of toxic protein aggregate species (oligomers or fibrils) is paramount for successful therapeutic development.
• Developing distinct modeling and therapeutic strategies for oligomers and fibrils is crucial for combating protein aggregation diseases.
• Future research should focus on precisely targeting the specific toxic aggregate species driving neurodegeneration.