Although the etiological event for idiopathic PD remains enigmatic, positive risk factors suggest the involvement of a multitude of factors including genetics, environmental exposure to toxins, and aging. Collectively, these influence the tempo and progression of disease (105
). The single greatest risk factor currently identified is age, which suggests cumulative CNS damage for disease pathogenesis. However, considerable variation among degenerative lesions in the SN of PD patients compared to aged non-PD patients, suggests that aging and the disease processes underlying PD may occur independently (141
). A significant body of evidence implicates ROS and RNS as possible initiating factors. The brain tissue itself is especially sensitive to oxidative damage, as this tissue accounts for 20% of the total oxygen demand of the body and is rich in peroxidizable fatty acids (20:4 and 22:6), while within the SN and basal ganglia, antioxidant defenses (i.e.
, catalase, superoxide dismutase, glutathione, and glutathione peroxidase) are the most sparse (43
); and the microglia, a primary source for reactive oxygen species which contribute to neuronal degeneration, are the greatest in number. illustrates the consequences of microglial activation and oxidative stress on neuronal physiology in PD. In part due to dopamine metabolism by endogenous enzymes such as monoamine oxidases (MAO) or by autooxidation that can yield H2
and dopamine-quinones, the neurons in the SN are especially vulnerable to oxidative stress (57
). Furthermore, the presence of transition metals, such as iron, has been shown to accelerate the auto-oxidation of dopamine (133
). Thus, the breakdown products of dopamine exacerbate inflammation and tissue damage by feeding H2
into the ROS cycle and/or by dopamine-quinone modification of protein sulfhydryl groups via nucleophilic additions. Subsequently, overproduction of free radicals such as superoxide and peroxynitrite feed into the ROS cycle to create an imbalance in the oxidation/reduction capacity of cells. Increased free radicals, without adequate antioxidant buffers in the SN, then react with proteins and nucleic acids to alter their functions, induce lipid peroxidation, or inhibit enzymes of the electron transport chain, eventually contributing to neuronal injury and death.
FIG. 1. Oxidative Stress and PD pathobiology. Free radicals can arise as a result of glial cell activation, mitochondrial dysfunction, or protein aggregation. Increased microglial activation is attributable to increased neuronal cell death and cell debris including (more ...)
Activation of mitochondrial-dependent programmed cell death pathways are found in postmortem PD brains and in rodent models of PD (113
). The mitochondrial apoptotic pathway involves mitochondrial outer membrane permeabilization leading to the release of cytochrome c, apoptosis-induced factor (AIF), endonuclease G, second mitochondria-derived activator of caspases (Smac), and high temperature requirement protein A2 (HTRA2)(151
). Inhibition of complex I of the electron transport chain (ETC), for instance with MPTP, results in a time-dependent and region specific increase in the soluble pool of cytochrome c in the mitochondrial intermembrane space that can be released into the cytosol by programmed cell death agonists such as Bax (113
). This occurs together with the release of caspase-9 and -3. Bax regulates SN pars compacta (SNpc) dopaminergic cell death associated with these caspases since their release coincides with Bax upregulation and translocation to the mitochondria, and caspase activation is prevented by genetic ablation of Bax (114
). Blocking caspase-9 or Apaf-1 also provides some degree of dopaminergic neuroprotection (101
). The importance of these events have been confirmed in PD as activation of Bax, caspase-9, and caspase-3 are detected in SNpc dopaminergic neurons of postmortem PD brains (64
). Additionally, reduction of complex I activity by 30% was described in idiopathic PD patients (110
). Complex I inhibition results in depletion of ATP and the inevitable impairment of all ATP-dependent cellular processes, as well as blocking the flow of electrons along the ETC which increases generation of free radicals that increase oxidative stress. Specifically, complex I inhibition causes oxidative damage by peroxidation of the inner mitochondrial lipid cardiolopin which affects the binding of cytochrome c to the inner mitochondrial membrane, leading to increases in the soluble cytochrome c pool of the mitochondrial intermembrane space. These factors leading to complex I inhibition most probably sensitize neurons to cell death agonists such as Bax.
Oxidative stress also damages mitochondria and proteosomes, while functional loss of the proteosome can also contribute to increased oxidative stress and induce neural apoptosis. Both oxidative stress and proteosome inhibition act in concert to promote protein fibril formation and accumulation of protein aggregates. Indeed, misfolded proteins are found in inclusion bodies associated with several neurodegenerative diseases (40
). In PD, the normally soluble, unfolded protein α-syn is found in intraneuronal cytoplasmic inclusions or “Lewy bodies” in aggregated form along with ubiquitin, and lipids. Alpha-synuclein structure contains a central hydrophobic region that contributes to its propensity to aggregate, but oxidative stress induced nitration also contributes to α-syn aggregation and protofibril formation. Dopamine stabilizes α-syn protofibrils by forming a dopamine-α-syn adduct (24
). Normally, misfolded proteins are ubiquitinated and degraded by the proteosome, but inhibition of this mechanism by oxidative stress allows greater accumulation of aggregated proteins. Furthermore, oxidative modification of α-syn can lead to self-aggregation and aggregation of other proteins, as well as damage to the ubiquitin–proteosome system. Importantly, aggregated α-syn has been shown to activate microglia leading to enhanced secretion of ROS (118
). Activation of microglia by nitrated α-syn (N-α-syn) may also diminish protective mechanisms against oxidative stress by lowering the cellular glutathione buffering capacity as demonstrated by diminished GSH levels, GSH/GSSG ratios, and total glutathione levels from microglia stimulated with N-α-syn (119
). The role of proteolytic stress in PD pathology is further supported by the observation that excess levels of parkin substrate proteins are found in a nonubiquitinated state in PD patients with mutations in the parkin gene (encodes an ubiquitin E3 ligase), and these mutations are associated with autosomal recessive juvenile parkinsonism (104
). Overexpression of α-syn in models and duplication or triplication in the wild-type gene in PD patients are associated with neurodegeneration and microglial activation, possibly because of the inability of the proteosome to handle the increased number of misfolded proteins. Taken together, these findings illustrate the close relationship between oxidative and proteolytic stress, microglial activation, and inflammation that may contribute to neuronal injury and cell death in PD.