Big versus small: The impact of aggregate size in disease

Brianna Hnath, Jiaxing Chen, Joshua Reynolds, Esther Choi, Jian Wang, Dongyan Zhang, Congzhou M. Sha, Nikolay V. Dokholyan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Protein aggregation results in an array of different size soluble oligomers and larger insoluble fibrils. Insoluble fibrils were originally thought to cause neuronal cell deaths in neurodegenerative diseases due to their prevalence in tissue samples and disease models. Despite recent studies demonstrating the toxicity associated with soluble oligomers, many therapeutic strategies still focus on fibrils or consider all types of aggregates as one group. Oligomers and fibrils require different modeling and therapeutic strategies, targeting the toxic species is crucial for successful study and therapeutic development. Here, we review the role of different-size aggregates in disease, and how factors contributing to aggregation (mutations, metals, post-translational modifications, and lipid interactions) may promote oligomers opposed to fibrils. We review two different computational modeling strategies (molecular dynamics and kinetic modeling) and how they are used to model both oligomers and fibrils. Finally, we outline the current therapeutic strategies targeting aggregating proteins and their strengths and weaknesses for targeting oligomers versus fibrils. Altogether, we aim to highlight the importance of distinguishing the difference between oligomers and fibrils and determining which species is toxic when modeling and creating therapeutics for protein aggregation in disease.

Original languageEnglish (US)
Article numbere4686
JournalProtein Science
Volume32
Issue number7
DOIs
StatePublished - Jul 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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