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Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons

Seung Yong Yoon1, Jung Eun Choi, Jin Myung Choi

  • 1Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.

Neuroscience Letters
|May 2, 2008
PubMed

Insights

In Alzheimer's disease models, inhibiting protein phosphatase 2A (PP2A) impairs microtubule (MT) transport. This deficit is linked to calpain-mediated dynein cleavage, causing neurite retraction.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Protein phosphatase 2A (PP2A) dysfunction is linked to Alzheimer's disease (AD) pathology, including tau hyperphosphorylation and microtubule (MT) instability.
  • Microtubule dynamics and transport are crucial for neuronal function and survival.

Purpose of the Study:

  • To investigate the impact of PP2A inhibition on microtubule stability and transport in primary cortical neurons.
  • To identify the molecular mechanisms underlying microtubule transport deficits induced by PP2A inhibition.

Main Methods:

  • Treatment of rat primary cortical neuron cultures with okadaic acid (OA), a PP2A inhibitor.
  • Immunocytochemistry to assess tubulin acetylation, tyrosination, and MT localization.
  • Analysis of dynein and dynactin cleavage by calpain.

Main Results:

  • Okadaic acid treatment reduced acetylated and detyrosinated tubulins while increasing tyrosinated tubulins.
  • MTs accumulated around the soma and proximal neurites, indicating impaired transport.
  • Calpain-mediated cleavage of dynein and dynactin was observed.
  • Inhibition of calpain activity rescued neurite shortening in OA-treated neurons.

Conclusions:

  • PP2A inhibition leads to MT transport deficits via calpain-mediated dynein cleavage.
  • This mechanism contributes to neurite retraction in a cellular model relevant to Alzheimer's disease.
  • Targeting calpain may offer a therapeutic strategy for AD-related neuronal degeneration.

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