Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease
- Author(s)
- Perier, C; Bove, J; Wu, DC; Dehay, B; Choi, DK; Jackson-Lewis, V; Rathke-Hartlieb, S; Bouillet, P; Strasser, A; Schulz, JB; Przedborski, S; Vila, M;
- Details
- Publication Year 2007-05-08,Volume 104,Issue #19,Page 8161-8166
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- NATL ACAD SCIENCES
- Keywords
- COMPLEX-I DEFICIENCY; BH3-ONLY PROTEINS; SUBSTANTIA-NIGRA; CELL-DEATH; NEURONAL APOPTOSIS; OXIDATIVE DAMAGE; CYTOCHROME-C; MEMBRANE PERMEABILIZATION; POLYMERASE ACTIVATION; BH3 DOMAINS
- Publisher's Version
- https://doi.org/10.1073/pnas.0609874104
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2007-05-08 12:00:00