Biochemical increase in phosphorylated alpha-synuclein precedes histopathology of lewy-type synucleinopathies

Lih Fen Lue, Douglas G. Walker, Charles H. Adler, Holly Shill, Hung Tran, Haruhiko Akiyama, Lucia I. Sue, John Caviness, Marwan N. Sabbagh, Thomas G. Beach

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

A key component in Lewy body (LB) pathology in LB disorders is α-synuclein phosphorylated at serine 129 (pαsyn). However, it is not known if increase in the level of biochemically measurable pαsyn precedes the presence of histologically identified Lewy-type synucleinopathy (LTS). To gain sights into possible temporal sequence, we measured levels of pαsyn in cingulate and temporal cortices that develop LTS pathology at later stages of LB disorders. Brain homogenates from 128 autopsy cases including normal controls and subjects classified by Unified LTS histopathology staging system were studied. We found that biochemically measurable pαsyn levels in cingulate and temporal cortices were significantly increased at Unified stages III and IV. When pαsyn levels were compared between LTS density scores instead of Unified stages, significant increases were detected even as LTS density scores increased from 0 to 1 in olfactory bulb and substantia nigra. Therefore, our findings demonstrated that changes of pαsyn levels in cingulate and temporal cortices coincided with the early appearance of the LTS pathology in olfactory bulb and substantia nigra, even though histologically demonstrable LTS was lacking in the cortical region. Therefore, identifying the underlying mechanisms driving these changes could be crucial to understanding the pathogenesis of LB disorders.

Original languageEnglish (US)
Pages (from-to)745-756
Number of pages12
JournalBrain Pathology
Volume22
Issue number6
DOIs
StatePublished - Nov 2012

Keywords

  • Lewy body disorder
  • Parkinson's disease
  • alpha synuclein
  • human brain
  • pathology staging
  • phosphorylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

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