Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease
Proceedings of the National Academy of Sciences. 2007-05-02; 104(19): 8161-8166
DOI: 10.1073/pnas.0609874104
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Dysfunction of mitochondrial complex I is associated with a wide spectrum of
neurodegenerative disorders, including Parkinson’s disease (PD). In rodents,
inhibition of complex I leads to degeneration of dopaminergic neurons of the
substantia nigra pars compacta (SNpc), as seen in PD, through activation of
mitochondria-dependent apoptotic molecular pathways. In this scenario, complex I
blockade increases the soluble pool of cytochrome c in the mitochondrial
intermembrane space through oxidative mechanisms, whereas activation of pro-cell
death protein Bax is actually necessary to trigger neuronal death by
permeabilizing the outer mitochondrial membrane and releasing cytochrome c into
the cytosol. Activation of Bax after complex I inhibition relies on its
transcriptional induction and translocation to the mitochondria. How complex I
deficiency leads to Bax activation is currently unknown. Using gene-targeted
mice, we show that the tumor suppressor p53 mediates Bax transcriptional
induction after PD-related complex I blockade in vivo, but it does not
participate in Bax mitochondrial translocation in this model, either by a
transcription-independent mechanism or through the induction of BH3-only proteins
Puma or Noxa. Instead, Bax mitochondrial translocation in this model relies
mainly on the JNK-dependent activation of the BH3-only protein Bim. Targeting
either Bax transcriptional induction or Bax mitochondrial translocation results
in a marked attenuation of SNpc dopaminergic cell death caused by complex I
inhibition. These results provide further insight into the pathogenesis of PD
neurodegeneration and identify molecular targets of potential therapeutic
significance for this disabling neurological illness.