Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein

J Neuropathol Exp Neurol. 2008 May;67(5):402-16. doi: 10.1097/NEN.0b013e31816fc995.


alpha-Synuclein (alpha-syn) is the major component of pathologic inclusions that characterize neurodegenerative disorders such as Parkinson disease, dementia with Lewy body disease, and multiple system atrophy. The present study uses novel phospho-specific antibodies to assess the presence and regulation of phosphorylated Ser87 and Ser129 in alpha-syn in human brain samples and in a transgenic mouse model of alpha-synucleinopathies. By immunohistochemistry, alpha-syn phosphorylated at Ser129, but not at Ser87, was abundant in alpha-syn inclusions. Under normal conditions, Ser129 phosphorylation, but not Ser87 phosphorylation, was detected at low levels in the soluble biochemical fractions in human alpha-syn transgenic mice and stably transfected cultured cells. Therefore, a role for Ser87 phosphorylation in alpha-synucleinopathies is unlikely, and in vitro assays showed that phosphorylation at this site would inhibit polymerization. In vitro studies also indicated that hyperphosphorylation of Ser129 alpha-syn in pathologic inclusions may be due in part to the intrinsic properties of aggregated alpha-syn to act as substrates for kinases but not phosphatases. Further studies in transgenic mice and cultured cells suggest that cellular toxicity, including proteasomal dysfunction, increases casein kinase 2 activity, which results in elevated Ser129 alpha-syn phosphorylation. These data provide novel explanations for the presence of hyperphosphorylated Ser129 alpha-syn in pathologic inclusions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Binding Sites / genetics
  • Casein Kinase II / chemistry
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Serine / chemistry
  • Serine / metabolism
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology
  • Substrate Specificity
  • Up-Regulation
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein
  • Serine
  • Casein Kinase II
  • Proteasome Endopeptidase Complex