Misfolding & Disease

Pin1 in Alzheimer's Disease Pathology

Summary

Pin1 is a unique peptidyl-prolyl isomerase that regulates protein conformation by catalyzing cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs. Its inactivation in Alzheimer's disease accelerates both tau tangles and Aβ plaque formation.

Key Points

  • 1Pin1 specifically targets phosphorylated Ser/Thr-Pro motifs
  • 2Converts pathological cis-tau to functional trans-tau
  • 3Reduces Aβ production by regulating APP processing
  • 4Oxidative inactivation of Pin1 accelerates AD pathology

Pin1 represents a unique intersection of proline chemistry and neurodegenerative disease, serving as a critical regulator of Alzheimer's disease pathology.

Pin1: A Unique Isomerase

Pin1 differs from other peptidyl-prolyl isomerases (PPIases) in a crucial way:

- Specifically recognizes phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motifs

  • Contains both a WW domain (substrate recognition) and a catalytic domain
  • Regulates proteins only after phosphorylation events

    • Role in Alzheimer's Disease

    Pin1 protects against AD pathology through two major mechanisms:

    1. Tau Regulation

    The tau protein contains multiple pSer/Thr-Pro motifs:

    - Phosphorylated tau exists predominantly in the cis conformation

    - Cis pT231-tau is aggregation-prone and pathological

  • Pin1 converts cis → trans, restoring function
  • Trans tau binds microtubules normally

    • - Trans configuration facilitates dephosphorylation by PP2A

    Result: Pin1 activity prevents neurofibrillary tangle formation.

    2. APP Processing

    Pin1 also regulates amyloid precursor protein (APP):

  • The cytoplasmic tail of APP contains pThr668-Pro
  • Pin1 regulates the conformation of this motif

    • - Trans conformation favors non-amyloidogenic processing

  • Processing by α-secretase prevents Aβ formation

    • - Cis conformation favors amyloidogenic pathway

    Result: Pin1 activity reduces Aβ production.

    Pin1 Inactivation in AD

    In Alzheimer's disease, Pin1 becomes inactivated:

    Oxidative Modification

    - The active site contains a critical cysteine (Cys113)

  • Reactive oxygen species (ROS) oxidize this residue
  • Oxidized Pin1 loses catalytic activity
  • AD brains show elevated oxidized Pin1

    • Consequences of Pin1 Loss

    When Pin1 is inactivated:

  • Tau remains in pathological cis conformation
  • Tau hyperphosphorylation persists
  • APP processing shifts toward Aβ production
  • Both hallmarks of AD are accelerated

    • Therapeutic Implications

    Pin1 represents a potential therapeutic target:

    - Restoring Pin1 activity could be neuroprotective

  • Antioxidant strategies might prevent Pin1 oxidation

    • - Cis pT231-tau antibodies (based on Pin1 substrate) show promise

  • Pin1-mimetic small molecules are under investigation
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