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Novel therapeutic strategies for neurodegenerative disease

Hitoshi Tanimukai1, Takashi Kudo, Toshihisa Tanaka

  • 1Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan. tanimuki@psy.med.osaka-u.ac.jp

Psychogeriatrics : the Official Journal of the Japanese Psychogeriatric Society
|July 17, 2009
PubMed

Insights

Protein phosphatase 2A (PP2A) dysfunction in Alzheimer's disease (AD) is linked to tau hyperphosphorylation. Inhibiting the breakdown of I(2)(PP2A) nuclear localization signal offers a potential therapeutic strategy for AD.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Protein phosphatase 2A (PP2A) activity is crucial for neuronal health.
  • Compromised PP2A activity and tau hyperphosphorylation are hallmarks of Alzheimer's disease (AD).
  • PP2A activity is regulated by endogenous inhibitor proteins, I(1)(PP2A) and I(2)(PP2A).

Purpose of the Study:

  • To investigate the role of I(2)(PP2A) in Alzheimer's disease pathogenesis.
  • To identify potential therapeutic targets for Alzheimer's disease based on I(2)(PP2A) regulation.

Main Methods:

  • Analysis of protein expression and localization in Alzheimer's disease brains.
  • Identification of the cleavage site within I(2)(PP2A).
  • Assessment of the nuclear localization signal (NLS) function of I(2)(PP2A) fragments.

Main Results:

  • I(1)(PP2A) and I(2)(PP2A) are upregulated in Alzheimer's disease brains.
  • Cleavage of I(2)(PP2A) holoprotein occurs, with its amino-terminal fragment translocating to the cytoplasm.
  • Translocated I(2)(PP2A) interacts with PP2A catalytic subunit and hyperphosphorylated tau.
  • The cleavage site is between amino acids 175 and 176, within a putative NLS (amino acids 168-181).

Conclusions:

  • Aberrant I(2)(PP2A) processing and cytoplasmic translocation contribute to Alzheimer's disease pathology.
  • The NLS region of I(2)(PP2A) is a critical target for therapeutic intervention.
  • Inhibiting the breakdown of the I(2)(PP2A) NLS may represent a novel treatment strategy for Alzheimer's disease.

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