The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration

Aging Cell. 2015 Oct;14(5):715-24. doi: 10.1111/acel.12359. Epub 2015 Jun 5.


Various neurodegenerative diseases are characterized by the accumulation of amyloidogenic proteins such as tau, α-synuclein, and amyloid-β. Prior to the formation of these stable aggregates, intermediate species of the respective proteins-oligomers-appear. Recently acquired data have shown that oligomers may be the most toxic and pathologically significant to neurodegenerative diseases such as Alzheimer's and Parkinson's. The covalent modification of these oligomers may be critically important for biological processes in disease. Ubiquitin and small ubiquitin-like modifiers are the commonly used tags for degradation. While the modification of large amyloid aggregates by ubiquitination is well established, very little is known about the role ubiquitin may play in oligomer processing and the importance of the more recently discovered sumoylation. Many proteins involved in neurodegeneration have been found to be sumoylated, notably tau protein in brains afflicted with Alzheimer's. This evidence suggests that while the cell may not have difficulty recognizing dangerous proteins, in brains afflicted with neurodegenerative disease, the proteasome may be unable to properly digest the tagged proteins. This would allow toxic aggregates to develop, leading to even more proteasome impairment in a snowball effect that could explain the exponential progression in most neurodegenerative diseases. A better understanding of the covalent modifications of oligomers could have a huge impact on the development of therapeutics for neurodegenerative diseases. This review will focus on the proteolysis of tau and other amyloidogenic proteins induced by covalent modification, and recent findings suggesting a relationship between tau oligomers and sumoylation.

Keywords: Alzheimer's disease; Huntington's disease; Parkinson's disease; covalent modification; neurodegeneration; small ubiquitin-like modifiers; tau oligomers; tauopathies; ubiquitin proteasome system; ubiquitination.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Models, Molecular
  • Neurodegenerative Diseases / metabolism*
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • tau Proteins / chemistry
  • tau Proteins / metabolism


  • tau Proteins
  • Proteasome Endopeptidase Complex