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4.1.3 Parkinson's Disease
PD is the second most common age-related neurodegenerative disorder after
AD. One percent of the population at the age of 65 or over is affected by PD
and the clinical symptoms are rigidity, resting tremor, and bradykinesia (94).
The degeneration of nigrostriatal doparminergic neurons found in the sub-
stantia nigra pars compacta (SNpc) results in these clinical symptoms, and a
40% reduction of the dopamine (DA) levels causes the first symptoms to come
up (95). Lewy bodies are the main histological marker of PD, which are formed
mostly of
-synuclein. This protein is generally accumulated in a polyubiqui-
tinated form and a missense mutation is responsible for the accumulation in
a familial PD (96, 97). Parkin is another protein which has a role in the forma-
tion of protein aggregates in PD (98). It normally functions as an E3-ligase in
the UPS, interacting with the RPN10 subunit of the 19S regulator of the 26S
proteasome (99). The third protein responsible in the aggregate formation is
the ubiquitin carboxy-terminal hydrolase L1, which is a deubiquitinating
enzyme found in neurons and hydrolyzes poly-Ub-sequences into single
monomers (100).
PD is found to be related to oxidative stress but it is still unknown if this is
one of the reasons or the result of the ongoing pathophysiology of the disease.
Superoxide, peroxynitrite, and hydrogen peroxide are the ROS found in PD.
DA itself is also a source of ROS due to its chemical instability and autoxida-
tion. The decomposition of DA results in superoxide formation, which is cata-
lyzed by metal ions due to high iron content of substantia nigra (101). Numerous
oxidative protein modifications were found in PD. 3-nitrotyrosine and the
concentration of nitrites were increased in the cerebrospinal fluid and in nigral
dopaminergic neurons in patients with PD (10, 102). In healthy subjects, post-
mortem samples of substantia nigra, basal ganglia, and prefrontal cortex were
tested regarding the protein carbonyl content, and substantia nigra was found
to possess twofold higher amounts compared with the other parts of the brain,
indicating the susceptibility of this particular brain part/tissue toward accumu-
lation of protein oxidation products (103). In the brain of patients with PD,
protein carbonyls were found to be increased in all brain regions, including
the substantia nigra, basal ganglia, globus pallidus, substantia innominata,
frontal cortex, and cerebellum (104). Protein carbonyls were also found in
patients with Lewy body dementia (105). Protein nitration was found to be
high in PD, demonstrated by increased 3-nitrotyrosine in Lewy bodies and in
amorphous deposits in intact and degenerating neurons in PD substantia nigra
(10). In the same study together with patients with AD, nitrate concentrations
in cerebrospinal fluid and nitrosyl adducts in brains of patients with patients
were found to be high (106). In addition, the nitration of manganese SOD was
found to be high in the cerebrospinal fluid (71). Peroxynitrite-induced modi-
fication of
-synuclein may play a role in Lewy body generation. Antibodies
for nitrated residues of
-synuclein were demonstrated to label Lewy bodies
in idiopathic PD, dementia with Lewy bodies, and in multiple system atrophy
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