Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of parkinson's disease

Mitochondrial dysfunction has been implicated in the pathogenesis of both idiopathic and familial Parkinson's disease (PD). Dopamine neurons in the substantia nigra exhibit autonomous pacemaking activity to maintain an optimal dopamine concentration in the striatum, resulting in the activation of energy metabolism. ATP production in neuronal cells is dependent on mitochondrial glucose oxidation, and reactive oxygen species (ROS) production associated with neuronal activation might be a major cause of mitochondrial damage in dopamine neurons. Alpha-synuclein, a major component of Lewy bodies, induces mitochondrial damage, and several genes responsible for familial PD encode molecules necessary for normal mitochondrial function. In addition, the auto-oxidation of dopamine produces dopamine quoinone and ROS. Astroglia provide neurons with lactate produced from glucose via glycolysis in response to neuronal activation. The co-activation of the pentose-phosphate pathway (PPP), a shunt pathway of glycolysis, in astroglia plays a pivotal role in protecting neurons against ROS with glutathione peroxidase and the reduced form of glutathione (GSH). In addition to the allosteric regulation of the PPP, which is associated with the activation of glycolysis, the PPP in astroglia can also be activated by ROS through the Kelch-like enoyl-CoA hydratase-associated protein 1 (KeapD/nuclear factor-erythroid 2 p45 subunit-related factor 2 (Nrf2) system. A rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PDH), is transcriptionally regulated by the Keapl/Nrf2 system, which is a master regulator of phase 2 detoxifying enzymes. ROS is thought to modify the thiol residue of Keapl and to facilitate Nrf2 dissociation from Keapl. Thereafter, Nrf2 translocates into the nucleus where it induces the transcription of G6PDH. The pharmacological activation of the Keapl/Nrf2 PPP in astroglia may provide a novel strategy for preventing the onset and progression of PD.