Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies

Am J Pathol. 2003 Jul;163(1):91-100. doi: 10.1016/s0002-9440(10)63633-4.


alpha-Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders in which abnormal inclusions containing alpha-synuclein accumulate in selectively vulnerable neurons and glia. In this report, immunohistochemistry demonstrates ubiquitin in subsets of alpha-synuclein inclusions in dementia with Lewy bodies and multiple system atrophy. Biochemistry demonstrates that alpha-synuclein in the sodium dodecyl sulfate-soluble fractions of diseased brains is ubiquitinated, with mono- and di-ubiquitinated species predominating over polyubiquitinated forms. Similar immunohistochemical and biochemical characteristics were observed in an A53T mutant human alpha-synuclein transgenic mouse model of neurodegenerative alpha-synucleinopathies. Furthermore, in vitro ubiquitination of alpha-synuclein fibrils recapitulated the pattern of alpha-synuclein ubiquitination observed in human disease and the A53T alpha-synuclein mouse model. These results suggest that ubiquitination of alpha-synuclein is not required for inclusion formation and follows the fibrillization of alpha-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Fractionation
  • Disease Models, Animal
  • Female
  • Gyrus Cinguli / cytology
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / pathology
  • Humans
  • Inclusion Bodies / chemistry
  • Inclusion Bodies / metabolism*
  • Lewy Body Disease / metabolism*
  • Lewy Body Disease / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Multiple System Atrophy / metabolism*
  • Multiple System Atrophy / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Spinal Cord / cytology
  • Spinal Cord / metabolism
  • Synucleins
  • Ubiquitin / metabolism*
  • alpha-Synuclein


  • Nerve Tissue Proteins
  • SNCA protein, human
  • Snca protein, mouse
  • Synucleins
  • Ubiquitin
  • alpha-Synuclein