Deciphering protein aggregation: Insights into morphology, contributing factors, and molecular pathologies

Adv Protein Chem Struct Biol. 2025:145:23-71. doi: 10.1016/bs.apcsb.2024.11.009. Epub 2025 Apr 2.

Abstract

Protein aggregation research stands at the cutting edge of biomedical science, offering crucial insights into the molecular underpinnings of neurodegenerative and amyloid-associated diseases. Significant advancements in deciphering the structural, biophysical, and molecular intricacies of protein misfolding are driving the development of innovative therapies. Emerging approaches, from small molecule inhibitors to sophisticated polymer-based therapeutics, hold great promise for alleviating the toxic impacts of aggregation with the potential to prevent, delay, or even reverse disease progression. Despite these advances, the field contends with substantial challenges. The polymorphic and complex nature of protein aggregates poses major obstacles to both research and therapeutic design. Yet, interdisciplinary methodologies-integrating advanced spectroscopic, imaging, and computational tools-are creating new pathways to address these complexities, effectively bridging molecular breakthroughs and practical therapeutic applications. The rapid shift of foundational discoveries to clinical trials marks a pivotal step forward, instilling new hope for patients with protein aggregation disorders. Each breakthrough propels us closer to life-changing therapies that may reshape the outlook for these patients. The promise of precise and effective treatments is driving a transformative shift in medical science, establishing protein aggregation research as a crucial pillar in combating these challenging diseases and offering a beacon of hope for the future of neurodegenerative care.

Keywords: Aggregation; Aggregation mechanisms; Amyloid fibrils; Oligomers; Steric zipper.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Neurodegenerative Diseases* / drug therapy
  • Neurodegenerative Diseases* / metabolism
  • Neurodegenerative Diseases* / pathology
  • Protein Aggregates*
  • Protein Aggregation, Pathological* / drug therapy
  • Protein Aggregation, Pathological* / metabolism
  • Protein Aggregation, Pathological* / pathology

Substances

  • Protein Aggregates