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Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+ -induced neurodegeneration

Daniele Cartelli1, Cristina Ronchi, Maria G Maggioni

  • 1Dipartimento di Biologia, Università degli Studi di Milano, Milan, Italy.

Journal of Neurochemistry
|July 24, 2010
PubMed

Insights

Parkinson's disease involves microtubule (MT) dysfunction. This study shows the neurotoxin MPP(+) impairs MT dynamics, leading to axonal transport deficits and neuronal death, supporting MTs' role in Parkinson's pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pathology

Background:

  • Microtubule (MT) system dysfunction is increasingly implicated in Parkinson's disease pathogenesis.
  • The neurotoxin 1-methyl-4-phenylpiridinium (MPP(+)) is a common tool to model Parkinsonian neurodegeneration.

Purpose of the Study:

  • To investigate the role of MT dysfunction in MPP(+)-induced dopaminergic neuron death.
  • To elucidate the sequence of events linking MT alterations to neurodegeneration.

Main Methods:

  • Analysis of tubulin post-translational modifications in PC12 cells exposed to MPP(+).
  • Live cell imaging to assess MT dynamics and reorientation.
  • Monitoring mitochondrial movement and varicosity formation along neurites.
  • Assessing caspase 3 activation and mitochondrial injury.

Main Results:

  • MPP(+) selectively reduces dynamic MTs and increases stable MTs.
  • MPP(+) exposure leads to reduced MT dynamics and reorientation.
  • Impaired axonal transport and mitochondrial accumulation precede caspase 3 activation and mitochondrial injury.
  • MT dysfunction was established before observable signs of cell injury.

Conclusions:

  • MPP(+)-induced neurodegeneration involves MT dysfunction.
  • Axonal transport impairment and mitochondrial damage are consequences of MT dysfunction in this model.
  • Alterations in MT organization and dynamics are pivotal in Parkinson's disease neuronal death.

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