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Author Notes:

Nicholas T Seyfried, Departments of Biochemistry and Neurology,Emory University School of Medicine, Atlanta, Georgia 30322. nseyfri@emory.edu

We are appreciative of John Hanfelt (Emory School of Medicine, Department of Biostatistics) for comments and critical reading of this manuscript.

The authors have no conflicts of interest to report.

Subjects:

Research Funding:

NTS is supported by an Alzheimer Association New Investigator Research Grant (NIRG12-242297).

This work was also supported by an NIH grants P50 (AG025688); P01 (AG014449); and mass spectrometry instrument time was subsidized by an Emory Neuroscience NINDS Core Facilities P30 grant (NS055077).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemical Research Methods
  • Biochemistry & Molecular Biology
  • IMAC
  • MS
  • Neurodegeneration
  • Proteostasis
  • Systems biology
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • ALPHA-B-CRYSTALLIN
  • LARGE GENE LISTS
  • IN-VIVO
  • MASS-SPECTROMETRY
  • HUMAN BRAIN
  • PHOSPHORYLATION
  • TAU
  • LOCALIZATION
  • PROTEOME

Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins

Tools:

Journal Title:

Proteomics

Volume:

Volume 15, Number 2-3

Publisher:

, Pages 508-519

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Abnormal phosphorylation contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), but may play other signaling roles during AD pathogenesis. In this study, we employed IMAC followed by LC-MS/MS to identify phosphopeptides from eight individual AD and eight age-matched control postmortem human brain tissues. Using this approach, we identified 5569 phosphopeptides in frontal cortex across all 16 cases in which phosphopeptides represented 80% of all peptide spectral counts collected following IMAC enrichment. Marker selection identified 253 significantly altered phosphopeptides by precursor intensity, changed by at least 1.75-fold relative to controls, with an empirical false discovery rate below 7%. Approximately 21% of all significantly altered phosphopeptides in AD tissue were derived from tau. Of the other 142 proteins hyperphosphorylated in AD, membrane, synapse, cell junction, and alternatively spliced proteins were overrepresented. Of these, we validated differential phosphorylation of HSP 27 (HSPB1) and crystallin-alpha-B (CRYAB) as hyperphosphorylated by Western blotting. We further identified a network of phosphorylated kinases, which coenriched with phosphorylated small HSPs. This supports a hypothesis that a number of kinases are regulating and/or regulated by the small HSP folding network.

Copyright information:

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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