Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease.
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.
Perier
Celine
C
Research Institute-University Hospital Vall d'Hebron, 08035 Barcelona, Spain.
Bové
Jordi
J
Wu
Du-Chu
DC
Dehay
Benjamin
B
Choi
Dong-Kug
DK
Jackson-Lewis
Vernice
V
Rathke-Hartlieb
Silvia
S
Bouillet
Philippe
P
Strasser
Andreas
A
Schulz
Jörg B
JB
Przedborski
Serge
S
Vila
Miquel
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D004249:DNA Damage; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology*; D020734:Parkinsonian Disorders / Q000473:pathology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D042967:Electron Transport Complex I