α-Synuclein fibrillation products trigger the release of hexokinase I from mitochondria: Protection by curcumin, and possible role in pathogenesis of Parkinson's disease.

Extensive research has shown that assembling of α-synuclein amyloid aggregates on mitochondria is an important mechanistic feature of Parkinson's disease (PD) and other Lewy body disorders. However, the molecular mechanism(s) of its neuronal toxicity remain unclear. Type 1 Hexokinase (HKI), a key enzyme in the control of brain glucose metabolism, plays an important role in protecting against mitochondrially-regulated apoptosis through reducing generation of reactive oxygen species (ROS). The release of mitochondrially-bound HKI causes a significant decrease in enzyme activity and triggers oxidative stress. Here, we have investigated the potency of amyloid fibrillation products arising from α-synuclein and hen egg white lysozyme (HEWL) for the release of HKI and ROS content enhancement in mitochondria isolated from rat brain. Results clearly indicate the capacity of the fibrillation products of α-synuclein, and not HEWL, to trigger release of HKI from the Type A binding site of mitochondria for the enzyme and to induce mitochondrial ROS enhancement in a dose-dependent manner. Moreover, we found that curcumin was very effective in preventing mitochondrial HKI release and ROS enhancement induced by α-synuclein fibrillation products. The pathophysiological significance of mitochondrial HKI activity and localization in pathogenesis of neurodegenerative disorders including PD are discussed. Taken together, these results may offer insight into a possible mechanism by which disease-related peptides and proteins may exert their neuronal toxicity.