Parkin-mediated lysine 63-linked polyubiquitination: A link to protein inclusions formation in Parkinson's and other conformational diseases?

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110 Scopus citations


Most, if not all, neurodegenerative diseases are marked by the presence of ubiquitin-positive protein inclusions. How proteins within these inclusion bodies escape proteasomal degradation despite being enriched with ubiquitin remains a conundrum. Current evidence suggests a relationship between proteasomal impairment and inclusion formation, a persuasive explanation for the inability of the cell to remove ubiquitinated protein aggregates. Alternatively, the formation of ubiquitin-enriched inclusion may be uncoupled from the proteasome. Supporting this, we recently uncovered a novel, proteasomal-independent, catalytic activity for the Parkinson disease (PD)-linked ubiquitin ligase, parkin, that significantly enhances the formation of Lewy body (LB)-like inclusions generated in cultured cells by the co-expression of α-synuclein and synphilin-1. This unique activity of parkin mediates a non-classical, lysine (K) 63-linked ubiquitin multichain assembly on synphilin-1 that is distinct from the classical, degradation-associated, K48-linked ubiquitination. Interestingly, two other PD-linked gene products, α-synuclein and UCHL1, have recently also been associated with K63-linked ubiquitination. Inclusive of parkin, there are therefore now three PD-related gene products that are known to potentiate K63-linked ubiquitination, thus signalling an important functional relationship between this unique mode of ubiquitin tagging and PD pathogenesis. Mechanistically, the involvement of a "non-degradative" mode of ubiquitination in protein inclusion formation is an attractive explanation for how proteins are seemingly stabilized within inclusions.

Original languageEnglish (US)
Pages (from-to)524-529
Number of pages6
JournalNeurobiology of aging
Issue number4
StatePublished - Apr 2006


  • Lewy body
  • Lysine-63
  • Parkin
  • Parkinson's disease
  • Proteasome
  • Ubiquitin
  • Ubiquitin proteasomal system

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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