How oxidative stress contributes to neurodegenerative diseases

OXIDATIVE STRESS AND NEURODEGENERATION 'Our research premise for therapeutic development,' explain Hyslop and Chaney, 'is that decreasing chemical energy supply and effective elimination of toxic waste products act synergistically to define the point at which a critical threshold for neurodegeneration is crossed.' GAPDH is widely distributed in tissues and, in addition to its metabolic function, it plays a role in other vital tasks, including DNA repair, regulation of gene expression, and controlled cell death, or apoptosis. Within the mitochondria and nucleus, translocated GAPDH (in addition to other important parallel signalling complexes), results in cellular stress response dictating cell fate decisions, either promoting neuronal survival or initiation of 'programmed cell death', referred to as apoptosis. When the active site cysteine of GAPDH is S-glutathionylated, S-glutathione binds tightly with neighbouring amino acids within the active site pocket, effectively inhibiting its removal and reactivation of and its role in apoptosis, providing insights to its role in inhibition of glucose metabolism and its accumulation in cardiovascular and neurodegenerative diseases.