Figure 1

A "Bermuda Triangle" of insults leads to neurondeath in PD. Known risk factors for the onset of Parkinson's disease (PD) include environmental (green), genetic (purple), and endogenous (blue) influences. Contributions from these risk factors trigger oxidative modifications, mitochondrial dysfunction, and impaired protein degradation that together form a "Bermuda triangle" of interrelated molecular events that underlie neurodegeneration. The interactions between these pathways are supported by the following (for details and citations, please refer to text): (1) Disturbances in mitochondrial respiration generate reactive oxygen species. (2) Overexpression of SOD is protective against mitochondrial toxins. (3) NOS deficiency or inhibition attenuates MPTP, paraquat, and rotenone toxicity. (4) Inhibition of degradation systems leads to increased sensitivity to oxidative stressors. (5) Impaired degradation leads to an accumulation of substrates, increasing the probability for oxidative modifications. (6) Excessive production of reactive oxygen and nitrogen species modifies proteins, leading to inactivation, crosslinking, and aggregation. (7) α-Synuclein modified by oxidized dopamine impedes CMA. (8) Oxidative modifications modify the lysosomal membrane and crosslink membrane proteins. (9) UPS and CMA are not able to unfold and remove oxidatively proteins. (10) Oxidative modification of proteasome subunits inhibits UPS function. (11) Macroautophagy is the principle mechanism for the degradation of damaged mitochondria. (12) Proteasome inhibition increases mitochondrial reactive species generation and decreases complex I and II activity.