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Chapter 1
Introductory Chapter - Genetic and Biochemical Factors
in Parkinson’s Disease
Jolanta Dorszewska and Wojciech Kozubski
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/64216
1. Introduction
Worldwide increased life expectancy, which was seen in the second half of the twentieth century,
has contributed to an increased number of cases of diseases typical of old age, including
Parkinson's disease (PD). At present, PD is one of the most common degenerative diseases of
the central nervous system (CNS) and affects nearly 2% of the population over the age of 65 and
5% over the age of 85. Moreover, the estimates show that in the face of population aging, the
number of patients with this neurodegenerative disease will maintain an upward trend.
Although PD was first described nearly 200 years ago, it is still an incurable disease and its
cause is not fully understood. It is known that disturbances in the structure of two pathological
proteins of PD, alpha-synuclein (ASN) and Parkin, may lead to the formation of Lewy bodies
(LB), which lead to damage of dopaminergic neurons and decreased levels of dopamine (DA).
The disturbances in the structure of ASN and Parkin are due to both genetic and environmental
factors. Despite numerous reports in the literature concerning the molecular basis of this
disease, little is known about the interactions occurring between the individual genes respon‐
sible for encoding these proteins and the pathological manifestation of PD [1–8].
As a result of the lack of knowledge of PD pathomechanism, it is also not possible to have
early, potentially intravital, diagnosis of this disease. Currently, the diagnosis of PD is based
on clinical criteria, supported with neuroimaging, and is only a probable diagnosis of this
disease. Reliable detection of PD is only possible after testing for the presence of neuropatho‐
logical changes in the brain that is typical for this disease and is carried out postmortem. It is
known that lack of early and definite diagnosis of PD may make it difficult to provide effective
therapy to slow down the progression of the disease and can decrease the quality of life of
patients [9].
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
2
Challenges in Parkinson's Disease
PD belongs to the disorders of the extrapyramidal system (EPS), in which we observe symp‐
toms in a number of nonmotor (NMS) symptoms, such as dementia, hallucinations, depres‐
sion, and orthostatic hypotension, in addition to motor disorders [9–12].
Many studies are currently being conducted on the pathogenesis of PD in many research
centers around the world, and knowledge of this disease is growing rapidly. In the last two
decades, new genes associated with PD (PARK1-PARK18) were discovered, and there was a
remarkable progress of surgical treatment techniques using deep brain stimulation (DBS) of
selected brain structures [6].
2. Genes important for pathogenesis of Parkinson’s disease
The causes of PD are both genetic and environmental. To date, a number of genes associated
with the presence of PD have been described within distinct patient families (familial PD, FPD)
and/or corresponding locations of genes identified as PARK (PARK1-PARK16) as described
in [5]. It is believed that genetic factors include mutations of the SNCA gene (PARK1, PARK4),
encoding the ASN protein, may also be responsible for increased susceptibility in sporadic PD
(SPD) [6,7].
It has been shown that approximately 5–10% of all known PD patients are people with FPD,
a monogenic condition that is classically inherited in a recessive or dominant manner. The
molecular mechanisms responsible for RPD also play an important role in the pathogenesis of
SPD.
Moreover, SPD occurs due to the influence of various factors, including signal transduction,
vesicular transport, the process of autophagy, and mitochondrial dysfunction. It is also
suggested that the clinical heterogeneity of PD, including SPD, may involve interactions not
only in genetic and environmental factors, as well as in the reactions between genes, such as
SNCA, PRKN, LRRK2, PINK1, and their protein products: ASN, Parkin, LRRK2, and PINK1,
respectively [1–8].
3. Oxidative damage and hyperhomocysteinemia and biogenic amines in
Parkinson’s disease
It is known that the degenerative process in PD occurs for many years before the manifestation
of clinical symptoms. There are several hypotheses to explain the pathological processes in
PD. One of them indicates the participation of oxidative stress in the damage that occurs to
dopaminergic neurons [13–15]. In oxidative neuron damage, it is possible that impaired
metabolism of homocysteine (Hcy) and other biothiols, such as methionine (Met), cysteine
(Cys), and glutathione (GSH), may be involved. Moreover, Hcy, or its oxidative product
homocysteine acid, may increase prooxidative activity, most probably through its direct
interaction with NMDA receptors (as agonist of NMDA receptor). Many of the literature
reports indicate that pathogenesis of PD is associated with increased apoptosis [13,15–18].
Introductory Chapter - Genetic and Biochemical Factors in Parkinson’s Disease
http://dx.doi.org/10.5772/64216
Homocysteine in physiological condition is converted to Met and Cys, depending on the
activity of enzymes MTHFR, MTR, MTHFD1, and CBS, encoded by genes MTHFR, MTR,
MTHFD1, and CBS, respectively [13]. Activity of these enzymes depends on the genotype of
the gene encoding a given enzyme. As also shown in [13], the following genotypes are included
in the pathogenesis of PD, for Hcy metabolites, Met [MTR, AA (A2756G)], Cys [MTR, AG
(A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T), and AA (A1298C), and GG (G1793A);
MTHFD1 AA (G1958A); MTR AA (A2756G)] and Hcy [MTHFR: CT (C677T) and GG (G1793A);
MTR, AG (A2756G)].
Biogenic amines are also involved in the generation of oxidative stress in the course of PD and
include catecholamines such as norepinephrine (NE), epinephrine (E), DA and serotonin (5HT). Catecholamines are subject to nonenzymatic autoxidation and form highly reactive
derivatives. Increased endogenous neurotoxin levels may lead to the formation of ubiquitin
and ASN-positive cytoplasmic inclusions (LB) [10–12]. Regulation of plasma biogenic amine
levels in PD affects both coding by genes the enzymes responsible for metabolism (COMT,
MAO-A and MAO-B), and the amines’ transport and reuptake (NET, DAT, SERT).
Polymorphisms in genes related to trading of biogenic amines may influence the manifestation
of this disease, especially NET GA (c.1287G>A) and NET AA (c.1287G>A) [12].
4. L-Dopa therapy effects in Parkinson’s disease
The strategy of therapy of patients with movement disorders, particularly PD, is based
essentially on the strengthening of dopaminergic transmission with exogenous L-dihydroxy‐
phenylalanine (L-dopa) and DA agonists [9]. It has been shown that long-term treatment of
PD patients with L-dopa improves their motor functions by increasing the level of central DA.
At the same time, it has been shown that increasing dopaminergic neuronal damage in PD
may reduce the effectiveness of L-dopa and DA agonist therapy. Moreover, in patients with
PD, due to the loss of dopaminergic neurons in the striatum, L-dopa may penetrate other
dopaminergic neurons, especially the mesolimbic, and lead to emotional and neuropsychiat‐
ric disorders in these patients.
L-Dopa therapy in PD may also induce cardiovascular disease and stroke by increasing the
plasma levels of risk factors for vascular diseases, such as asymmetric dimethylarginine
(ADMA) and Hcy. Moreover, L-dopa leads to increased levels of 8-oxo-2’-deoxyguanosine (8oxo2dG), a parameter of oxidative stress, and changes levels of biogenic amines and pro‐
teins involved in apoptosis [9,15,19–21].
5. Summary
Although PD has been known and studied since the early nineteenth century, the cause of
death of dopaminergic neurons remains unknown and the treatment of this disease focuses
on treating symptoms.
3
4
Challenges in Parkinson's Disease
In PD, as in other neurodegenerative diseases, research seeks to determine biomarkers to
enable early definite diagnosis of this disease and the development of effective neuroprotec‐
tive or modulatory disease drugs. PD patients who do not respond to conventional drug
treatment are currently treated using one of the new surgical techniques, including DBS.
Currently, research in PD is looking for a therapy that can ensure effective antiparkinsonian
treatment, eliminate dyskinesia, and slow or stop the progression of this disease.
Author details
Jolanta Dorszewska1* and Wojciech Kozubski2
*Address all correspondence to: dorszewskaj@yahoo.com
1 Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical
Sciences, Poznan, Poland
2 Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan,
Poland
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