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Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease

Chun-Hau Chen1, Wenzong Li2, Rukhsana Sultana3

  • 1Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Neurobiology of Disease
|January 11, 2015
PubMed

Insights

Pin1 enzyme oxidation at Cys113 inactivates its function, contributing to Alzheimer's disease (AD) pathology. Preventing this Pin1 oxidation may offer a new therapeutic strategy for AD.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Pin1 (prolyl isomerase) is crucial for preventing age-dependent neurodegeneration and Alzheimer's disease (AD).
  • Pin1 undergoes oxidative modification in human AD brains, but the mechanisms and significance remain unclear.
  • Pin1 links tau tangle and amyloid plaque pathologies in AD.

Purpose of the Study:

  • To elucidate the mechanisms and pathological significance of Pin1 oxidative modification in Alzheimer's disease.
  • To identify specific oxidation sites on Pin1 and their functional consequences.
  • To investigate the role of Pin1 redox regulation in neuronal survival and AD pathogenesis.

Main Methods:

  • Crystal structure determination of oxidized Pin1.
  • Generation of antibodies specific to oxidized Cys113 of Pin1.
  • In vitro enzymatic assays to assess catalytic activity.
  • Point mutation analysis (Cys113 to Alanine).
  • Assessment of subcellular localization and neuronal survival under hypoxia.

Main Results:

  • Oxidative modification of Pin1 occurs sequentially at Cys113.
  • Pin1 oxidation at Cys113 inactivates its isomerase activity and impairs tau and APP turnover.
  • Cys113-oxidized Pin1 shows altered subcellular localization and reduced neuronal survival under hypoxia.
  • Levels of Cys113-oxidized Pin1 are significantly elevated in human AD brains compared to controls.

Conclusions:

  • Cys113 is identified as a critical catalytic residue for Pin1 activity, and its oxidation serves as a novel inhibitory mechanism in AD.
  • Oxidative inactivation of Pin1 contributes to Alzheimer's disease pathology.
  • Targeting and preventing Pin1 oxidation presents a potential therapeutic avenue for reducing AD risk.
Keywords:
APPAlzheimer's diseaseOxidationPin1Tau

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