Published online before print August 3, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070015

Accepted for publication June 19, 2007.

Article

Quantitative Proteomics Identifies Surfactant-Resistant -Synuclein in Cerebral Cortex of Parkinsonism-Dementia Complex of Guam but Not Alzheimer's Disease or Progressive Supranuclear Palsy

Wan Yang^*, Randall L. Woltjer^*, Izabela Sokal^*, Catherine Pan^*, Yan Wang^*, Mary Brodey, Elaine R. Peskind, James B. Leverenz, Jing Zhang^*, Daniel P. Perl, Douglas R. Galasko^¶, and Thomas J. Montine^*@

From the Department of Pathology,* Division of Neuropathology, University of Washington, Seattle, Washington; Biosource Division, Invitrogen, Camarillo, California; Veteran's Administration Puget Sound Health Care System, Mental Illness Research, Education, and Clinical Center, and Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington; the Neuropathology Division, Mount Sinai School of Medicine, New York, New York; and the Department of Neurosciences,^¶ University of California, San Diego, California

^@ To whom correspondence should be addressed. E-mail: tmontine{at}u.washington.edu.

	Abstract

Parkinsonism-dementia complex (PDC) remains a significant health burden to the Chamorro population. We tested the hypothesis that quantitative proteomics might provide fresh insight into this enigmatic illness by analyzing proteins resistant to surfactant extraction from patients with Alzheimer's disease (AD) or PDC and their matched controls using isobaric tags for relative and absolute quantification. In addition to the expected increase in abnormal frontal cortical A peptides, tau, ubiquitin, and apolipoprotein E in AD, and tau in PDC, we identified -synuclein (SNCA) as a major abnormal protein in PDC but not AD. We confirmed our isobaric tags for relative and absolute quantification findings by enzyme-linked immunosorbent assay in frontal and temporal cortices. We extended our assays to include a limited number of cases of progressive supranuclear palsy (PSP) and dementia with Lewy bodies; we observed increased abnormal tau but not SNCA in PSP, and abnormal SNCA in dementia with Lewy bodies that was quantitatively similar to PDC. Finally, soluble A oligomers were selectively increased in AD but not PDC or PSP. These results show that frontal and temporal cortex in PDC is distinguished from AD and PSP by its accumulation of abnormal SNCA and suggest that PDC be considered a synucleinopathy as well as a tauopathy.