Pathology of PD. Despite the complex nature of PD, two pathological features of PD are observed in most idiopathic PD patients: loss of dopaminergic (DA) neurons in the substantia nigra and presence of Lewy bodies (LBs) or lewy neurites (LNs) in the surviving neurons (128). DA neurons in the nigrostriatal pathway are more susceptible to cell death than other neurons or DA neurons in other brain regions, possibly due to the detrimental effect of dopamine metabolism. DA neurons in the nigostriatal pathway contain neuromelanin, giving rise to the distinct dark pigment. In PD brain samples, the substantia nigra regions look pale compared to normal human brain samples. Other pigmented nuclei (locus cerulues, dorsal motor nucleus of the vagus) could also be affected. The degeneration of DA neurons is followed by replacement with glia cells in that region (128). LBs and LNs are cytoplasmic inclusion bodies enriched in proteins and components of the ubiquitin machinery. They are eosinophilic spherical inclusions surrounded by a halo and usually immunostained positive for α-synuclein. LBs are not restricted to PD, they are also seen in other neurodegenerative disorders such as Lewy body dementia, suggesting that the pathological pathways contributing to the formation of LBs are shared by various neurodegenerative disorders (128). In addition to DA neurons in SN, other neuronal regions and neurons of other transmitter systems also contain LBs and LN. The susceptible neurons appear to be projection neurons that have a disproportionately long axon in relation to the size of the cell soma, especially those with axons poorly myelinated (35,36). The sparsely myelinated neurons require more energy to transmit impulses and are subjected to higher levels of oxidative stress. The surrounding of oligodendroglial cells may also protect neurons from pathological sprouting. Since other brain regions and neurotransmitter systems are also affected in PD, a staging system has been developed based on α-synucleon pathology to delineate the sequential involvement of different type of neurons (35,36). The pathogenic relevance of LBs to PD is still under debate. Since LBs contain misfolded proteins and exist in patients with neurodegenerative disorders, they were initially thought to be toxic. However, recent findings suggest that formation of LBs may be a cellular self-defense mechanism by which misfolded proteins are isolated from the rest of cells and are prevented from attacking important cellular c...
