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BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP

Anthony K F Liou1, Zhigang Zhou, Wei Pei

  • 1Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. lioukf@upmc.edu

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 9, 2005
PubMed

Insights

MPP+ triggers Parkinson's disease-like dopaminergic cell death via BimEL, calpain I, and apoptosis-inducing factor (AIF) release. This caspase-independent pathway highlights a novel mechanism in neurodegeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Parkinson's disease (PD) involves dopaminergic neuron loss.
  • MPP+ is a neurotoxin used to model PD.
  • Understanding cell death mechanisms is crucial for PD therapeutics.

Purpose of the Study:

  • To elucidate the signaling pathway of MPP+-induced dopaminergic cell death.
  • To investigate the roles of BimEL, calpain I, and apoptosis-inducing factor (AIF) in this process.

Main Methods:

  • Utilized neuronal-differentiated PC12 cells as a model system.
  • Investigated the effects of MPP+ treatment on gene and protein expression (JNK, c-jun, BimEL).
  • Assessed calpain I activity, mitochondrial AIF release, and cell viability using knockdown and inhibition strategies.

Main Results:

  • MPP+ treatment increased BimEL expression via JNK and c-jun.
  • BimEL upregulation enhanced calpain I activity, leading to AIF release and cell death.
  • Knocking down BimEL or inhibiting calpain I reduced AIF release and cell death.
  • Activated calpain I directly induced AIF release from mitochondria in cell-free conditions.

Conclusions:

  • MPP+-induced dopaminergic cell death involves a novel, caspase-independent pathway.
  • This pathway is characterized by BimEL upregulation, subsequent calpain I activation, and mitochondrial AIF release.
  • Targeting calpain I may offer a therapeutic strategy for Parkinson's disease.

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