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 have also identified the mechanisms underlying Bax activation in experimental PD, which involves the coordinated activation of c-Jun N-terminal kinase and p53 molecular pathways secondary to oxidative DNA damage, and demonstrated that targeting specific molecules of these deleterious pathways by genetic manipulation in mutant mice results in a neuroprotective effect. In addition, in collaboration with a pharmaceutical company, we have developed a new compound able to inhibit Bax activation in vivo and demonstrated the feasibility and therapeutic potential of pharmacologically targeting Bax-induced membrane permeabilization to attenuate neurodegeneration linked to PD.

Mitochondria-dependent apoptosis. Apoptosis can result from the activation of two distinct molecular cascades, known as the extrinsic (or death receptor) and the intrinsic (or mitochondrial) pathways. Both pathways, which can converge at the level of mitochondria, involve the activation of initiator caspases (caspase-8 and -9, respectively) that catalyze the proteolytic maturation of downstream executioner caspases, such as caspase-3, which are the final effectors of cell death. Mitochondrial outer membrane permeabilization (MOMP) represents the point-of-no-return in the mitochondrial apoptotic pathway. Following MOMP, mitochondrial apoptogenic factors such as cytochrome c, Smac/Diablo, endonuclease G or apoptosis-inducing factor (AIF) are released to the cytosol. Once into the cytosol, these factors can initiate cell death in a caspase-dependent or a caspase-independent manner. Released cytochrome cinteracts with two other cytosolic protein factors, Apaf-1 and procaspase-9, to activate caspase-3. Smac/Diablo can interact with several inhibitors of apoptosis (IAPs), thereby relieving the inhibitory effect of IAPs on initiator (e.g. caspase-9) and effector (e.g. caspase-3) caspases. AIF and endonuclease G can translocate to the nucleus and induce caspase-independent DNA fragmentation. MOMP is highly regulated by anti-apoptotic (e.g. Bcl-2 and Bcl-xL) and pro-apoptotic (e.g. Bax and Bak) protein members of the Bcl-2 family. Structurally, all these proteins share up to four Bcl-2-homology domains (BH1–BH4). In addition to multidomain Bcl-2 family members, there are molecules that share sequence homology only with the BH3 domain (such as Bid, Bim, Puma and Noxa) that can induce cell death either by activating multidomain pro-apoptotic proteins or by inactivating anti-apoptotic proteins. Bid is activated following its cleavage by caspase-8, thus linking the extrinsic and intrinsic pathways at the level of the mitochondria. While several components of the mitochondrial apoptotic pathway have been implicated in the pathogenesis of PD, the participation of the extrinsic pathway in PD has not been consistently demonstrated. AIF, apoptosis-inducing factor; Casp-9, caspase-9; CL, cardiolipin: OPA1, optic atrophy type 1; Cyt. c, cytochrome c; EndoG, endonuclease G; IAP, inhibitor of apoptosis; tBid, truncated Bid. From Perier & Vila, Cold Spring Harbor Perspectives in Medicine (2012).

Additional reading:

Mitochondria and programmed cell death in Parkinson’s disease: apoptosis and beyond.
Perier C., Bové J. and Vila M.
Antioxidants & redox signaling 16(9):883-95 (2012)

Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease.
Perier C., Bové J., Wu D.C., Jackson-Lewis V., Dehay B., Choi D.G., Rathke-Hartlieb S., Bouillet P., Strasser A., Schulz J.B., Przedborski S. and Vila M.
Proceedings of the National Academy of Sciences USA 104(19):8161-6 (2007)

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)

Targeting programmed cell death in neurodegenerative diseases.
Vila M. and Przedborski S.
Nature Reviews in Neuroscience, 4(5):365-75 (2003)

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)