Programmed Cell Death

Although multiple pathogenic pathways may lead to PD-related neurodegeneration, it is likely these diverse pathways converge on the common mechanisms of cell death. These cell death pathways normally function to degrade and clear cells after traumatic damage (necrosis) or at the ends of their life cycles (programmed cell death, including apoptosis and autophagy) (Recipi et al., 2007).

Apoptosis is a mechanism of programmed cell death during which a cell goes through various morphological changes including membrane blebbing, cell shrinkage, nuclear condensation, and DNA fragmentation. Apoptosis is carried out by enzymes (caspases) that physically dismantle the cell. When functioning normally, this highly controlled mechanism avoids triggering potentially harmful responses, such as inflammation. It remains unclear whether apoptosis is the primary mechanism of cell death in PD neurodegeration. However, numerous apoptotic pathways are activated in response to PD-induced dysfunction in other systems, including JNK signaling, p53 activation, cell cycle re-entry, and bcl-2 family signaling. Caspase activation, a hallmark of apoptosis, has also been reported in neurodegeneration (Levy et al., 2009).

Autophagy ("self-eating") is a process during which intracellular organelles are digested by lysosomes. It is thought to function as a starvation response, allowing a cell to scavenge nutrient from non-vital components, but can also be a mechanism of programmed cell death. However, it remains unclear whether autophagy is pathological or protective in Parkinson's disease. Autophagy may act as an initial protective response, but is eventually overwhelmed and pushed towards cell death during disease progression (Ferucci et al., 2008).