Parkinson's Disease ... (Parkinson 's disease) - Genes GBA, LRRK2, PARK2, PARK7, PINK1, SNCA and UCH - L1.

Parkinson's disease is a progressive disorder of the nervous system. The disorder affects several brain regions, especially the substantia nigra that controls balance and movement. Often the first symptom of the disease is the tremor of a limb, especially it is at rest. Usually, the shaking starts on one side of the body, usually in one hand. Tremors can also affect the arms, legs, feet and face. Other characteristic symptoms of Parkinson's disease include rigidity or stiffness of the limbs and trunk, bradykinesia or akinesia, and postural instability. These symptoms slowly worsen over time. Parkinson's disease can also affect emotions and consciousness. Some affected individuals develop psychiatric illnesses such as depression and visual hallucinations. Those affected also at increased risk of developing dementia.

Most cases of Parkinson's disease are probably the result of a complex interaction of environmental and genetic factors. These cases are classified as sporadic and occur in people with no apparent history of the disease in your family. The cause of these sporadic cases remains unclear. About 15 percent of people with Parkinson 's disease have a family history of this disorder. Familial cases of Parkinson's disease can be caused by mutations in the GBA, LRRK2, PARK2, PARK7, PINK1, SNCA and UCH - L1. Alterations in certain genes, such as GBA and UCH - L1 not cause Parkinson's disease, but seem to modify the risk of developing the disease in some families.

Not fully understand how genetic changes cause Parkinson's disease or influence the risk of developing the disorder. Many of the symptoms of Parkinson's disease occurs when neurons die or become impaired. Normally, these cells produce dopamine, a chemical messenger that transmits signals within the brain for smooth physical movements. When dopamine neurons are damaged or die, communication between the brain and the muscles weaken. Eventually, the brain loses the ability to control muscle movement. Some gene mutations appear to disrupt the machinery of the cell that breaks into dopamine - producing neurons. As a result, undegraded proteins accumulate, leading to failure or death of these cells. Other mutations can affect the function of mitochondria. As a byproduct of energy production, mitochondria produce free radicals that can damage cells. Cells normally counteract the effects of free radicals before they cause damage, but mutations can disrupt this process. As a result, free radicals can accumulate and impair or kill dopamine - producing neurons.

The GBA gene, located on the long arm of chromosome 1 (1q21), encoding the enzyme beta-glucocerebrosidase. This enzyme is active in lysosomes, using enzymes to decompose toxic substances, digesting bacteria that invade the cell, and recycle cell components. On the basis of these functions, lysosomal enzymes called hurt cleaning enzymes. Beta-glucocerebrosidase is an enzyme cleaning helps break down glucocerebroside to glucose and ceramide molecule. Changes in this gene can contribute to the defective breakdown of toxic substances in nerve cells by altering the function of lysosomes. Alternatively, changes may increase the formation of deposits of abnormal proteins. As a result, toxic substances, or protein deposits could accumulate and kill nerve cells produce dopamine, resulting in abnormal movements and balance problems.

The LRRK2 gene, located on the long arm of chromosome 12 (12q12), is active in the brain and other tissues throughout the body. This gene encodes the protein dardarina. A segment dardarin protein called leucine - rich region, appears to play a role in the activities that require interactions with other proteins, such as signaling or configuration of the cytoskeleton. It is also believed that other parts of the protein are involved in dardarina protein-protein interactions. Additional studies indicate that dardarin has a function of enzyme known as kinase activity, which helps the transfer of a phosphate group from ATP molecule to amino acids of some proteins. This transfer of phosphate (phosphorylation), and is an essential step in the activation and deactivation of many cellular activities. Dardarin also has a second function of GTPase activity. This activity is associated with a region of a protein called the domain ROC, which helps control the shape of the dardarina protein. They have identified more than 100 mutations in the LRRK2 gene causing the disease. Most mutations replace individual amino acids in dardarin protein which affects the structure and function of the protein. Other mutations, replacing the amino acid arginine for glycine in protein position 1441 (Arg1441Gly or R1441G), the amino acid glycine by serine at 2019 position (Gly2019Ser or G2019S) or cause the replacement of glycine by arginine at 2385 position (Gly2385Arg or G2385R). It is unclear how mutations in the LRRK2 gene causes problems of movement and balance characteristic of Parkinson's disease.

The PARK2 gene, located on the long arm of chromosome 6 (6q25.2-q27), encoding parkin protein. This protein plays a role in cell degradation by marking damaged proteins and excess ubiquitin molecules. Ubiquitin acts as a signal to move the proteins that are not necessary in proteasomes, which proteins are degraded. The ubiquitin-proteasome system acts as quality control of the cell. This system also regulates the availability of proteins that are involved in several critical cellular activities, such as the timing of cell division and growth. Parkin protein appears to be involved in maintaining mitochondria, helping to promote their destruction when they are not working properly. Additionally, it is thought that parkin protein may act as a tumor suppressor protein and may regulate the availability and synaptic vesicle release between nerve cells, which contain the chemical messengers which transmit signals from one nerve cell to another. There are more than 200 mutations in the gene cause the disease PARK2. Mutations in this gene are associated with the juvenile form of Parkinson's disease, which appears before age 20, and some cases of the most common, late - onset which starts after 50 years. Some mutations result parkin molecule abnormally small which is not functional and is rapidly degraded within cells. Other mutations inserted, deleted or changed nucleotides in the gene, resulting in a defective version of parkin protein or preventing the production of this protein. Mutations in the gene may also disrupt PARK2 regulation of mitochondria. Researchers speculate that mitochondrial dysfunction in dopamine - producing nerve cells can play an important role in the cause of the signs and symptoms of Parkinson's disease.

The PARK7 gene, located on the short arm of chromosome 1 (1p36.23), encoding the DJ-1 protein. This protein is found in many tissues and organs, including the brain. One function of the protein is cell protection from oxidative stress, especially in brain cells. Oxidative stress occurs when unstable free radical molecules accumulate to levels that can damage or kill cells. Moreover, the DJ-1 protein can serve as a chaperon molecule that helps fold proteins newly produced in the proper 3-dimensional shape and helps replicate damaged proteins. They have identified more than 25 mutations in the gene PARK7 that can cause disease. These mutations are associated with early onset form of the disease, which begins before 50 years. Some mutations lead to an abnormally small or change the amino acids of the protein DJ-1 protein. The altered protein is unstable and not work properly. Other mutations eliminate a large part of the gene, preventing the production of any functional DJ-1 protein.

The PINK1, located on the short arm of chromosome 1 (1p36), encoding the PTEN protein. This protein is found in cells throughout the body, with the highest concentrations in the heart, muscle and testes. Within cells, the protein is found in mitochondria. PTEN function is not fully understood. It is thought that helps protect mitochondria malfunction during periods of cellular stress, when there is an unusually high demand for energy. They have identified more than 70 mutations in the PINK1 gene cause the disease. These mutations are associated with early - onset form of the disease. Many of these genetic changes alter or eliminate the kinase domain, causing a loss of protein function. At least one mutation affecting mitochondrial targeting motif, which may interrupt the penetration of the protein into the mitochondria. With a reduced or absent PTEN activity, mitochondria can go wrong, especially when cells are stressed. Cells can die if they are not providing power for essential activities. It is unclear how mutations PINK1 cause selective death of nerve cells that characterize Parkinson's disease. The loss of these cells weakens the communication between the brain and muscles, and ultimately the brain becomes unable to control muscle movement.

The SNCA gene, located on the long arm of chromosome 4 (4q21), encoding the protein alpha-synuclein. This protein is abundant in the brain, being smaller amounts in heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly in presynaptic terminals. Within these structures, alpha-synuclein interacts with lipids and proteins. Presynaptic terminals release neurotransmitters that transmit signals between neurons and are essential for normal brain function. Found at least 18 SNCA gene mutations cause the disease. They described two types: a type change a single amino acid in the alpha-synuclein. In some cases, the amino acid alanine is replaced with threonine at position 53 protein (Ala53Thr) or proline at position 30 (Ala30Pro). These mutations cause alpha-synuclein assume a tridimensional shape incorrectly. In other alteration, one of the two SNCA genes in each cell is doubled or tripled, leading to an excess of alpha-synuclein impairing the functioning of neurons in specific brain regions.

The UCH - L1 gene, located on the short arm of chromosome 4 (4p14), encodes esterase enzyme ubiquitin carboxyl-terminal L1, found in nerve cells throughout the brain. Ubiquitin serves as a signal for dsplazar proteins that are not necessary in proteasomes, where they are broken. The ubiquitin-proteasome system acts as a quality control system of the cell by removing damaged or excess proteins. Although the exact role of ubiquitin carboxyl terminal esterase L1 is not fully understood, it appears to have two types of activity. One, the hydrolase activity, removes and recycles ubiquitin molecules from degraded proteins. Ligase activity other function, binds ubiquitin molecules for labeling proteins for disposal. Mutations in this gene replacing the amino acid isoleucine with the amino acid methionine at position 93 in the ubiquitin carboxyl-terminal esterase L1 (Ile93Met or I93M). The mutation leads to reduced activity of hydrolase, which can alter the ubiquitin-proteasome system. Instead of being degraded, unnecessary proteins could accumulate to toxic levels that damage or destroy nerve cells in the brain. The loss of these cells weakens the communication between the brain and muscles, and ultimately the brain becomes unable to control muscle movement.

Most cases of Parkinson 's disease occur in people with no family history of the disease. These sporadic cases can not be inherited, or may have a pattern of inheritance is unknown. Among the familial cases of Parkinson's disease, the inheritance pattern differs depending on which gene is altered. If involved the LRRK2 gene or the SNCA gene, the disorder is inherited as an autosomal dominant inheritance, meaning that one copy of the altered gene in each cell is sufficient to cause disease. In most cases, an affected person has a parent with the disorder. If they are involved PARK2, PARK7 or PINK1 genes, Parkinson's disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. When genetic alterations modify the risk of developing Parkinson's disease, the pattern of inheritance is generally unknown.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with Parkinson's disease, by complete PCR amplification of the exons of the GBA, LRRK2, PARK2, PARK7, PINK1, SNCA and UCHL1 respectively genes and subsequent sequencing .

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).