REACTIVE SPECIES - Oxidation of Amino Acids, Peptides, and Proteins: Kinetics and Mechanism - page 6

Figure 1.2. Complex I deficiency may be central to sporadic PD (adapted from Dawson
and Dawson [43] with the permission of the American Association for the Advance-
ment of Science).
and survival in the pathogenesis of both sporadic and familial PD [44]. The
role of ROS in sporadic PD is shown in Figure 1.2 [43]. Derangements in
complex I (NADH CoQ10 reductase) and oxidative stress lead to aggregation
and accumulation of α-synuclein [43]. Dysfunction of complex I results in
the formation of free radicals and a decrease in the level of the formation of
ATP, which ultimately result in neuronal depolarization and excitotoxic neu-
ronal injury. The involvement of RNS also increases oxidative stress and injury
(see Fig. 1.2) [45].
The role and significance of glutathione (GSH) in PD has been studied in
detail [36, 37, 46]. A cell has a redox equilibrium, which involves GSH and
GSH disulfide [47]. Under oxidative stress, the equilibrium moves toward
disulfide and, hence, depletes GSH. A significant decrease in levels of GSH in
SN has been observed in PD, which lowers the activity of the mitochondrial
complex I [48-50]. This process accelerates the buildup of defective proteins,
which impairs the ubiquitin-proteasome pathway during protein degradation,
resulting in cell death of the SN dopaminergic neurons. The presence of abnor-
mal protein aggregates is a characteristic of neurodegeneration during PD. The
role of iron in PD has been reported [49, 51]. Iron transporters, divalent metal
transporter 1 (DMT1) and ferroportin, may be involved in dopaminergic brain
areas where the production of H 2 O 2 favors the Fenton reaction. The chelation
of iron may be effective in preventing or delaying the progression of PD [52].
1.1.2 Metals in Human Diseases
In biological systems, redox metals such as Cu, Fe, Cr, and Co are involved in
redox cycle reactions and generate reactive intermediates like O •− and NO • ,
which cause the disruption of homeostasis. This creates an excess amount of