Research
Targeting programmed cell death in Parkinson’s disease
Programmed cell death (PCD), a physiological process that occurs naturally during development in which molecular programs intrinsic to the cell are activated to cause its own destruction, is inappropriately re-activated in Parkinson’s disease (PD), causing dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc). In particular, we have shown that activation of the mitochondria-dependent apoptotic pathway is instrumental in the neuronal degeneration associated with disruption of mitochondrial respiration caused by complex I deficiency in experimental PD. However, complex I blockade is not the actual executioner but rather sensitizes neurons to mitochondrial-dependent apoptosis through oxidative damage and activation of the pro-apoptotic Bcl-2 family member Bax. According to this scenario, free radical production, secondary to complex I blockade, increases the ‘‘releasable’’ soluble pool of cytochrome c into the mitochondrial intermembrane space through peroxidation of the inner mitochondrial lipid cardiolipin, while activated Bax triggers cell death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c to the cytosol. In agreement with this, genetic targeting of Bax in mutant mice prevents dopaminergic neurodegeneration caused by complex I inhibition in experimental PD. We are currently exploring the mechanisms that activate and regulate PCD pathways in PD in order to identify new molecular targets of potential therapeutic significance to attenuate, or even prevent, dopaminergic neurodegeneration.
Additional reading:
Targeting programmed cell death in neurodegenerative diseases.
Vila M. and Przedborski S.
Nature Reviews in Neuroscience, 4(5):365-75 (2003)
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.
Perier C., Tieu K., Guegan C., Caspersen C., Jackson-Lewis V., Carelli V., Martinuzzi A., Hirano M., Przedborski S. and Vila M.
Proceedings of the National Academy of Sciences USA, 102(52):19126-19131 (2005)
Bax ablation prevents dopaminergic neurodegeneration in the MPTP mouse model of Parkinson´s disease.
Vila M., Jackson-Lewis V., Vukosavic S., Djaldetti R., Liberatore G., Offen D., Korsmeyer S.J. and Przedborski S.
Proceedings of the National Academy of Sciences USA, 98(5):2837-2842 (2001)
