Detergent insoluble proteins and inclusion body-like structures immunoreactive for PRKDC/DNA-PK/DNA-PKcs, FTL, NNT, and AIFM1 in the amygdala of cognitively impaired elderly persons

Jozsef Gal, Jing Chen, Yuriko Katsumata, David W. Fardo, Wang Xia Wang, Sergey Artiushin, Douglas Price, Sonya Anderson, Ela Patel, Haining Zhu, Peter T. Nelson

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Misfolded protein in the amygdala is a neuropathologic feature of Alzheimer disease and many other neurodegenerative disorders. We examined extracts from human amygdala (snap-frozen at autopsy) to investigate whether novel and as yet uncharacterized misfolded proteins would be detectable. Polypeptides from the detergentinsoluble, urea-soluble protein fractions of amygdala were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. Among the detergent-insoluble proteins identified in amygdala of demented subjects but not controls were Tau, TDP-43, Aβ, α-synuclein, and ApoE. Additional detergent-insoluble proteins from demented subjects in the high-molecular weight portion of SDS gels included NNT, TNIK, PRKDC (DNA-PK, or DNA-PKcs), ferritin light chain (FTL), AIFM1, SYT11, STX1B, EAA1, COL25A1, M4K4, CLH1, SQSTM, SYNJ1, C3, and C4. In follow-up immunohistochemical experiments, NNT, TNIK, PRKDC, AIFM1, and FTL were observed in inclusion body-like structures in cognitively impaired subjects' amygdalae. Doublelabel immunofluorescence revealed that FTL and phospho-PRKDC immunoreactivity colocalized partially with TDP-43 and/or Tau inclusion bodies. Western blots showed high-molecular weight "smears", particularly for NNT and PRKDC. A preliminary genetic association study indicated that rare NNT, TNIK, and PRKDC gene variants had nominally significant association with Alzheimer-type dementia risk. In summary, novel detergent-insoluble proteins, with evidence of proteinaceous deposits, were found in amygdalae of elderly, cognitively impaired subjects.

Original languageEnglish
Pages (from-to)21-39
Number of pages19
JournalJournal of Neuropathology and Experimental Neurology
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2018

Bibliographical note

Publisher Copyright:
© 2017 American Association of Neuropathologists, Inc.

Keywords

  • ADSP
  • GWAS
  • LC-MS
  • Lewy
  • Phosphorylation
  • Proteomics
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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