Stress Response Pathways

PD involves profound cellular stresses, and thus stress response pathways play an important role in PD progression. Also, it has been hypothesized that PD may indeed be triggered by pathological responses to cellular stress. Numerous endogenous pathways are activated as cytoprotective mechanisms in response to cellular stresses, both internal (DNA damage, oxidative stress, etc.) and external (starvation, hypoxia, etc.) Specific endogenous sensors can activate global responses (activating heat shock proteins and other protective machinery) to either repair or compensate for stress-inducing stimuli, or to initiate cell death as an organismal protective measure.

mTOR kinase is a highly conserved protein regulating numerous cellular pathways, including growth, proliferation, survival, motility, protein synthesis, and autophagy. mTOR is sensitive to external energy levels, responding to growth factor signaling, nutrient conditions, and starvation as well as to internal energy levels and redox conditions. In PD research, mTOR is usually targeted for its role in inhibiting autophagy.

The transcription factor Nrf2 binds to the antioxidant response element (ARE) in gene promoters, and is reported to be a major regulator of cytoprotective responses including both antioxidant and anti-inflammatory proteins (Johnson et al., 2008; Li and Kong, 2009; Zhang, 2006).

Additionally, genetic mutations associated with PD (such as DJ-1) can affect the functionality of these pathways.