From Science Online

Contents 1 Introduction 2 Signs 3 Diagnosis 4 Causes 5 Biochemistry 5.1 Treatment 5.2 Research

Introduction

Parkinson's Disease is a disorder of the brain. It is caused by the impairment or death of certain neurones in the part of the brain known as the substantia nigra.

(Medline Plus National Library of Medicine)

Parkinson's Disease usually affects people over the age of 50 and early symptoms are subtle and occur gradually. In some people the disease progresses more quickly than in others. (National Institute of Neurological Disorders and Stroke) While the condition usually develops after the age of 65, 15% of those diagnosed are under 50. (National Parkinson Foundation)

Although Parkinson's Disease isn't fatal, it progresses with time and the average life expectancy of a patient is generally lower than for people without the disease. In the late stages of the disease, complications may occur such as choking, pheumonia, and falls that could lead to death.

Signs

There are motor symptoms and non-motor symptoms. Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual. The most common symptoms include:

• Tremor (shaking) • Slowness of movement • Rigidity (stiffness) • Difficulty with balance • Small, cramped handwriting • Stiff facial expression • Shuffling walk • Muffled speech • Depression

(National Parkinson Foundation)

Diagnosis

Unfortunately, there are currently no tests available, whether blood tests or laboratory tests, to detect Parkinson's disease. MRIs, CATs and EEGs all produce normal results as the brain changes that create neurodegenerative diseases such as Parkinson's are microscopic, on a chemical level. Doctors observe patients' movement, coordination and balance and so usually look for shuffling of feet, a tremor when their limb is relaxed (As many as 25% of Parkinson's patients, however, will not have a tremor.), symptoms on one side of the body (about.com), and lack of swing in the arms.

Causes

The primary symptoms of Parkinson's disease are due to excessive muscle contraction and the overall effect of dopamine is to inhibit muscle contraction. Dopamine is produced in the dopaminergic neurons, however these cells don't reproduce and this results in irreversible cell loss in Parkinson's Disease.

Dopamine is formed in the following way: L-tyrosine → L-dopa → dopamine The first step is biosynthesised by the enzyme tyrosine 3-monooxygenase and the following equation summarisez the complete reaction: L-tyrosine + THFA + O2 + Fe2+ → L-dopa + DHFA + H2O + Fe2+ For L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and ferrous iron are essential. The activity of this enzyme is often as low as 25% in Parkinson's disease, and in severe cases can be as low as 10%. This indicates that one or more of the elements required for the formation of L-dopa are in insufficient quantities. The second step in the biosynthesis of dopamine is biosynthesised by the enzyme aromatic L-amino acid decarboxylase. The following is the complete reaction: L-dopa + pyridoxal phosphate → dopamine + pyridoxal phosphate + CO2 So for dopamine biosynthesis from L-dopa, pyridoxal phosphate is essential. The activity of the enzyme rises and falls according to how much pyridoxal phosphate there is. The level of this enzyme in Parkinson's disease can also be around 25% or even far less.

In the cells involved in Parkinson's disease (the dopaminergic neurons) the function is to produce dopamine. In the melanocytes, which are in the skin, the function is to produce the pigment melanin. Melanin is what causes people to suntan. Although they end up with different substances (dopamine and melanin), both of these cells start off with L-tyrosine, and both of them form L-dopa as well: dopaminergic neurons : L-tyrosine > L-dopa > dopamine melanocytes : L-tyrosine > L-dopa > melanin In the dopaminergic neurons, when somebody can not form dopamine, they can accidentally form melanin instead. In the brain it is called neuromelanin because of the different amino acids it is attached to. However, this is not a normal mechanism, and it occurs via a different mechanism from that found in the skin. The formation of neuromelanin in the brain is often claimed to be what happens in healthy brains. Healthy brains are supposed to be darker in the part of the brain called the substantia nigra. However, it is actually due to the biochemical mechanisms not working properly. As not much L-dopa is formed in Parkinson's disease, there isn't much capacity for that L-dopa to accidentally form melanin in the brain. So people with Parkinson's disease can tend to have not much pigment in the part of the brain called the substantia nigra. However, that does not cause a medical problem because melanin is not supposed to be in the brain. (VIARTIS)

One theory suggests that Parkinson's Disease results from the combination of a gentically determined vulnerability to environmental toxins along with exposure to those toxins. The toxins most strongly suspected at present are certain pesticides and transition-series metals such as manganese or iron, especially those that generate reactive oxygen species, and/or bind to neuromelanin, as originally suggested by G.C.Cotzias. (Wikipedia) In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of Parkinson's Disease than individuals who were not exposed.

Biochemistry

A key feature in Parkinson’s disease is the deposition of Lewy bodies. The major protein component of these intracellular deposits is the 140-amino acid protein α-synuclein that is widely distributed throughout the brain. α-synuclein was identified in presynaptic terminals and in synaptosomal preparations. The protein is remarkable for its structural variability. It is almost unstructured as a monomer in aqueous solution. Self-aggregation leads to a variety of β-structures, while membrane association may result in the formation of an amphipathic helical structure. (Beyer, 2007)

This is alpha -synuclein. Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Dominant mutations in the gene encoding α-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin (a highly conserved regulatory protein expressed in eukaryotes) ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, how the recessive genes relate to α-synuclein, or whether they represent different ways to induce a similar phenotype, has not yet been fully resolved. (Cookson, 2005)

Their pathological correlate is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Although there are many other neuronal groups affected in different brain regions in Parkinson's Disase (Dauer, 2003), nigral degeneration and resultant parkinsonism is a consistent feature of all the genetic conditions discussed here. Secondly, Parkinson's Disease is marked postmortem by the presence of Lewy bodies (LBs) and Lewy neurites in surviving neurons. These are intracellular aggregations of lipids and proteins that were first identified by eosin staining and now by immunostaining for their protein components including ubiquitin and α-synuclein.Parkinson's disease is a disease composed of two parts: parkinsonism and Lewy pathology. α-synuclein is both part of Lewy pathology and a cause of dominantly inherited disease.

All synucleins have a series of imperfect repeats including the sequence motif KTKEGV and a variable C-terminal tail, which is highly acidic in α-synuclein. Synucleins are also basally phosphorylated at serine and tyrosine residues.There is little or no detectable secondary structure in solution, and hence α-synuclein is referred to as natively unfolded.The functions of the synucleins are not well understood. α-Synuclein binds to lipid membranes, forming an amphipathic helix (Clayton, 1998). Given the location of a pool of α-synuclein at synaptic membranes, there may be a synaptic role for the protein. The first α-synuclein mutation thatwas discovered is an A53T point substitution (Polymeropoulos, 1997). An unusual aspect of the mutation is that the amino acid is already a threonine in rodents and other species. Subsequently, three additional mutations have been found: A30P in German kindred, E46K in a Spanish kindred, and a riplication of the wild-type gene in a large family from Iowa (Singleton, 2003). Pathology from three of these kindreds is available and shows α-synuclein-positive Lewy bodies in the brainstem as well as nigral cell loss.

Image:Pic.bmp

β-pleated sheet-like bonding stabilizes the aggregated forms. This contrasts with the unstructured protein in solution or folding when bound to lipid, earning α-synuclein the title of “a protein chameleon” (Uversky, 2003). A central hydrophobic region of α-synuclein, near the repeats, tends to self-associate, contributing to aggregation. This region is not shared with (for example) β-synuclein, and consequently these homologues vary radically in their propensity to aggregate. In fact, β-synuclein can prevent α-synuclein aggregation in vivo (Hashimoto, 2001) and in vitro (Park, 2003). The C-terminal acidic tail of α-synuclein inhibits aggregation and, hence, truncated forms are more prone to aggregate . This ability of wild-type α-synuclein to aggregate presumably explains its presence in the several sporadic synucleinopathies. The end product of α-synuclein aggregation is the formation of heavily insoluble polymers of protein known as fibrils. It is thought that fibrillar α-synuclein is the building block of Lewy bodies. α-Synuclein is also the most sensitive marker for Lewy bodies, implying that it is necessary for Lewy body formation (Sampathu, 2003).

There are rare inherited autosomal dominant cases that are associated with point mutations in the αS gene. An A53T mutation was first identified in a large kindred of Italian and Greek origin. Later, two other point mutations, A30P and E56K, were found in German and Spanish families, respectively. Both, the A53T and the A30P mutations lead to accelerated formation of protein oligomers, while only the A53T variant protein readily forms large amyloid fibrils. The E46K mutant binds to negatively charged vesicles with a higher protein/lipid ratio than the wild type protein, and seems to be even more effective than the other mutations in promoting the formation of high molecular weight aggregates in a catecholaminergic cell line.

The single amino acid variants may aggravate an intrinsic nucleation propensity of the protein. As an alternative, the amino acid replacements may impair membrane binding and coil-helix transition of αS which may then redirect the unstructured protein into the aggregation pathway. Overproduction of the protein may also account for aggregation which is a nucleation-dependent process that requires a minimum concentration of the monomer. Multiplication of the αS gene is indeed associated with different phenotypes of PD which may be a consequence of a persistently enhanced αS monomer level. (Beyer, 2007)

pdb code 1PS4

(Huai, 2003)

This is the crystal structure of DJ-1, an RNA binding protein. The pink areas define the alpha helices and the yellow areas define the beta sheets. In total, there are eight alpha helices and 11 strands contributing to beta sheets.

DJ-1 is a protein involved in multiple physiological processes, including cancer, Parkinson`s disease, and male fertility. It is unknown how DJ-1 functions in the apparently different systems. The crystal structure of DJ-1 at 1.6 A resolution shows that DJ-1 is a helix-strand-helix sandwich and forms a dimer. The DJ-1 structure is similar to the members of the intracellular protease PfpI family. However, the catalytic triad of Cys-His-Glu is not strictly conserved in DJ-1, implying that DJ-1 has a different catalytic mechanism if it acts as a protease or DJ-1 serves as a regulatory protein in the physiological processes. The structure shows that Leu166 positions in the middle of a helix and thus predicts that the L166P mutation will bend the helix and impact the dimerization of DJ-1. As a result, the conformational changes may diminish the DJ-1 binding with its partner, leading to the familial Parkinson`s disease caused by the single L166P mutation. (Huai, 2003)

Treatment

Although there is no cure for Parkinson's Disease, certain medication, physiotherapy and surgery can provide relief from symptoms.

Levodopa is a commonly prescribed medication. It is modified by brain enzymes to produce dopamine and reduces the symptoms of slowness, stiffness and tremor and to date remains the most effective treatment for many of the symptoms of Parkinson disease. Since blood enzymes (called AADCs) would break down most of the levodopa before it reached the brain, it is always combined with either an enzyme inhibitor called carbidopa or benserazide. Once it has been converted into dopamine, it is subsequently released by brain cells and activates dopamine receptors allowing for normal function of the movement control centers of the brain. (National Parkinson Foundation)

Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all. Anticholinergics may help control tremor and rigidity. Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine. An antiviral drug, amantadine, also appears to reduce symptoms. ()

Replacement dopamine Therapy isn't all good news however. Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning.(Giovannoni, 2000)

Dominant mutations in the gene encoding alpha-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, we have not yet fully resolved how the recessive genes relate to alpha-synuclein, or whether they represent different ways to induce a similar phenotype. (Information hyperlinked over proteins)

Vitamin C and vitamin E have been used to try to help to prevent cell damage in Parkinson's Disease. This is because they are claimed to assist in two enzyme reactions in the brain that get rid of the superoxide anion once it has been formed. Coenzyme Q10 has more recently been used for similar reasons. (VIARTIS)

Surgery tends to be used in people with advanced Parkinson's Disease for whom drug therapy is no longer sufficient. Deep brain stimulation is presently the most used surgical means of treatment, but other surgical therapies that have shown promise include surgical lesion of the subthalamic nucleus and of the internal segment of the globus pallidus, a procedure known as pallidotomy.(Wikipedia)

Research

Current research programs funded by the NINDS are using animal models to study how the disease progresses and to develop new drug therapies. Scientists looking for the cause of PD continue to search for possible environmental factors, such as toxins, that may trigger the disorder, and study genetic factors to determine how defective genes play a role. Other scientists are working to develop new protective drugs that can delay, prevent, or reverse the disease.

References