Oligomers of α-synuclein in the pathogenesis of Parkinson's disease

Dong Pyo Hong, Wenbo Zhou, Aaron Santner, Vladimir N. Uversky

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Misfolding and subsequent self-assembly of proteins into various aggregates is a common molecular mechanism in a number of important human diseases. Understanding the peculiarities of the protein-misfolding processes is essential for the design of successful drugs that inhibit or reverse protein aggregation, leading to protein-misfolding pathologies. Protein aggregation is a complex process characterized by remarkable polymorphism, where soluble amyloid oligomers, amyloid fibrils, and amorphous aggregates are found as the final products. This polymorphism is associated with existence of multiple, independent, and competing assembly pathways leading to aggregation. Irrespectively of aggregation mechanisms, soluble oligomers inevitably form during the self-association processes. Some of these oligomers are now considered major initiators of the pathogenic neurodegenerative cascades in the corresponding diseases. However, not all oligomers are equally harmful, and several amyloidogenic proteins form non-toxic oligomers, some of which are efficient fibrillation inhibitors. Unfortunately, information on the structural properties of soluble oligomers and mechanisms of their formation, inter-conversion, and toxicity is sparse. This chapter provides an overview of some topics related to soluble oligomers and several illustrative examples of toxic, non-toxic, productive, and off-pathway amyloid oligomers. The peculiarities of soluble oligomers of α-synuclein and its relation to the pathogenesis of Parkinson's disease are also discussed.

Original languageEnglish (US)
Title of host publicationNon-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases
PublisherSpringer Netherlands
Pages189-216
Number of pages28
Volume9789400727748
ISBN (Electronic)9789400727748
ISBN (Print)9400727739, 9789400727731
DOIs
StatePublished - Mar 1 2012

Keywords

  • Aggregation mechanism
  • Amyloid fibril
  • Protein deposition diseases
  • Soluble oligomer
  • α-synuclein

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