For many years, it was thought that most forms of Parkinson’s disease did not have a genetic basis. But by the late 1990s, studies in a number of patient populations documented that the risk of Parkinson’s disease among first-degree relatives of an affected individual is 2 to 14 times higher than the risk in the general population. As genome technologies have become more cost-effective and precise, genetic linkage maps have improved dramatically, allowing more research into the genetic cause of disease. Entire genome sequence analyses are now being completed on individual patients at a reasonable and ever-dropping price.

There are a small number of genes that are known to be involved in up to 6% of total PD cases, and there are probably other genes that increase the potential risk of Parkinson’s, without necessarily causing it. Up to 15% of PD patients have a direct family member who has also had PD.

PARK Family of Genes

A gene family is a group of genes that share important characteristics. The PARK gene family has been of particular interest and is the focus of widespread research. Mutations in PARK genes affect the function and survival of nerve cells critical for normal movement, balance, and coordination (NIH, 2013a).

Mutations in three known genes (SNCA, UCHL 1, and LRRK 2) have been reported in families with dominant inheritance. Mutations in three other genes (PARK 2, PARK 7, and PINK 1) have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson’s disease (recessive inheritance). There is some evidence to suggest that these genes are also involved in early-onset Parkinson’s disease (diagnosed before the age of 30) or in dominantly inherited Parkinson’s disease but it is too early to be certain (genome.gov, 2011).

The following table lists the genes in the PARK family with their approved symbol in the first column and their previous names in the middle column. The approved symbols are used in this section of the course.

Dominant Genes in PD

Mutations in a group of genes that encode alpha-synuclein and LRRK 2 are transmitted in a dominant fashion and generally lead to Lewy body pathology, with alpha-synuclein being the major component of these pathologic protein aggregates (Greggio et al., 2011). Although genetic tests can test for the presence of the LRRK 2 mutation, they cannot be used to make a definitive diagnosis of PD.

SNCA

The discovery of mutations in the SNCA gene was the first evidence of a genetic cause for PD. This gene encodes the protein alpha-synuclein, the main component of Lewy bodies and the noted pathology marker in autopsy slides of PD brains. Mutations of the SNCA gene, including nucleotide changes, and duplications, triplications, and extra copies of the SNCA gene, account for about 2% of familial cases, though not all persons with these changes have developed PD. The mean age of onset in individuals with mutations in this gene is 46 years (Greggio et al., 2011).

Recent studies have demonstrated that alpha-synuclein regulates the release of neurotransmitters at the presynaptic terminal. In addition, alpha-synuclein seems to modulate intracellular dopamine concentration through interactions with proteins that regulate dopamine synthesis and uptake (Greggio et al., 2011).

LRRK 2 (PARK8)

The LRRK 2 gene (formerly PARK8) is a signaling protein that becomes toxic when it mutates (Greggio et al., 2011). The LRRK 2 gene encodes for a protein called dardarin. One segment of the dardarin protein contains a large amount of an amino acid called leucine. Proteins with leucine-rich regions appear to play a role in activities that require interactions with other proteins, such as transmitting signals or helping to assemble the cell’s structural cytoskeleton. Other parts of the dardarin protein are thought to be involved in protein-to-protein interactions (NIH, 2013a).

Nearly a dozen different mutations have been reported in the LRRK 2 gene. Mutations in LRRK 2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. Sergey Brin, one of the two noted co-founders of Google, has a known mutation in this autosomal dominant gene for PD, with the resulting 20% to 80% chance of developing PD. His mother, Genia Brin, carrying the same mutation, was diagnosed with PD in 1998 at the age of 50.

Recessive Genes in PD

Mutations in PARK2 (parkin), PINK1 (PARK 6), and DJ-1 (PARK7) cause recessive Parkinson’s, with a variable pathology often lacking the characteristic Lewy bodies in the surviving neurons. Intriguingly, recent findings highlight the role of these genes in mitochondria function, suggesting a common molecular pathway for recessive Parkinson’s (Greggio et al., 2011).

PARK2 (Parkin)

The PARK2 gene, one of the largest human genes, provides instructions for making a protein called parkin, which plays a role in the breakdown of unneeded proteins. It does this by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to move unneeded proteins into specialized cell structures known as proteasomes, where the proteins are degraded (NIH, 2013a).

The ubiquitin-proteasome system acts as the cell’s quality control by disposing of damaged, misshapen, and excess proteins. This system also regulates the availability of proteins that are involved in several critical cell activities, such as the timing of cell division and growth. Because of its activity in the ubiquitin-proteasome system, parkin belongs to a group of proteins called E3 ubiquitin ligases (NIH, 2013a).

Parkin also appears to be involved in the maintenance of mitochondria, the energy-producing centers in cells. Genetic and cell biologic work in the last decade have uncovered essential roles of parkin and PINK1 in mitochondrial quality control. PINK1 senses damaged mitochondria and recruits and activates parkin to degrade and recycle damaged mitochondria. Much evidence suggests that defects in this pathway may cause PD (Wauer & Komander, 2013).

A great deal of research has focused on the Parkin gene. In early 2013, in a significant breakthrough, the crystal structure of parkin was identified, providing new insight into the function of this important gene. According to Jennifer Johnson, one of the researchers involved with the discovery of the crystal structure of parkin, “The crystal structure acts as a sort of blueprint for parkin’s function. Scientists can see exactly how it works, and then begin to develop compounds to target areas of dysfunction, and then better see if compounds applied to trouble areas are making a difference” (MJFF, 2013).

Studies of the structure and activity of parkin have led researchers to propose several additional roles for this protein. Parkin may act as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Parkin may also regulate the supply and release of synaptic vesicles from nerve cells.

The parkin type of juvenile-onset Parkinson’s disease, originally described in Japan, is characterized by typical Parkinson’s disease features with onset between age 20 and 40 years. Disease progression is slow and lower-limb dystonia is often present, which causes muscles to contract and spasm involuntarily. Sustained response to levodopa is observed, as well as early, often severe dopa-induced complications (e.g., fluctuations, dyskinesias).

PINK1 (PARK6)

More than seventy mutations that can cause Parkinson’s disease have been found in the PINK1 (PARK6) gene. Interestingly, when fruit flies carrying PINK1 mutations were given vitamin K2, the energy production in their mitochondria was partly restored and the insects’ ability to generate energy to fly was improved. Researchers have been able to determine that the energy production was restored because the vitamin K2 had improved electron transport in the mitochondria. This in turn led to improved adenosine triphosphate (ATP) and energy production for flight. Vitamin K2 plays a role in the energy production of defective mitochondria. Because defective mitochondria are also found in some Parkinson’s patients, vitamin K2 potentially offers hope for a new treatment for Parkinson’s (NIH, 2013a).

DJ-1 (Park7)

The PARK7 gene provides instructions for making the DJ-1 protein. This protein is found in many tissues and organs, including the brain. One of the protein’s functions may be to help protect cells, particularly brain cells, from oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells. Additionally, the DJ-1 protein may serve as a chaperone molecule that helps fold newly produced proteins into the proper three-dimensional shape as well as helping refold damaged proteins (NIH, 2013a).

The DJ-1 protein may also assist in delivering selected proteins to proteasomes, which are structures within cells that break down unneeded molecules. Researchers suggest that the DJ-1 protein may also play a role in activities that produce and process RNA, a chemical cousin of DNA (NIH, 2013a).

Genetic Testing

The term genetic testing covers an array of techniques including analysis of human DNA, RNA, and protein. Genetic tests are used to detect gene variants associated with a specific disease or condition, as well as for nonclinical uses such as paternity testing and forensics. In the clinical setting, genetic tests can be performed to:

• Confirm a suspected diagnosis
• Predict the possibility of future illness
• Detect the presence of a carrier state in unaffected individuals (whose children may be at risk)
• Predict response to therapy

Genetic tests are also performed to screen fetuses, newborns, or embryos used in in vitro fertilization for genetic defects (NHGRI, 2013).

Genetic testing has recently become available for the parkin and PINK1 genes. But because parkin is such a large gene, testing is difficult. At the current stage of understanding, testing is likely to give a meaningful result only for people who develop the condition before the age of 30 years (NHGRI, 2011).

PINK1 appears to be a rare cause of inherited Parkinson’s disease. About 2% of those developing the condition at an early age appear to carry mutations in the PINK1 gene. Genetic testing for the DJ-1 (PARK7), SNCA and LRRK2 genes is also available (NHGRI, 2011).

Individuals and families who are interested in genetic testing can learn more about their risk for Parkinson’s disease and the availability and accuracy of genetic testing by contacting a genetics specialist. Genetics professionals provide information and support to individuals or families who have genetic disorders or who may be at risk for inherited conditions, and can discuss the risks, benefits, and limitations of available genetic testing for Parkinson’s disease (NHGRI, 2011).

Gene Therapy

Gene therapy is “the use of genes as medicine” involving the transfer of a therapeutic or working copy of a gene into specific cells in order to repair a faulty gene or to give the cell a new function (Centre for Genetics Education, 2012). The most effective vector or carrier of a therapeutic gene is a very small virus that does not cause inflammation or an immune response.

Before a therapeutic gene can be inserted into a patient, the gene’s viral genetic material is removed and replaced with the therapeutic gene. The altered virus is then injected into a specific part of the brain where it deposits its genetic material. Once in the brain, it infects the target cells and releases its gene (Aminoff, 2010).

In Parkinson’s disease, which is related to the deficiency of dopamine and treated with an oral medication, injecting a gene into a discrete area of the brain may allow the cells in that area to produce more of the missing neurotransmitter. Gene therapy has two advantages over oral medications:

1. It reduces side effects associated with dopamine replacement, which when taken orally stimulates dopamine receptors all over the brain, leading to unwanted side effects.
2. It has the potential to provide a steady supply of the missing neurotransmitter, an improvement over an oral tablet, whose levels increase when the medication is taken and then decrease as the medication wears off (Aminoff, 2010).

Surgical Insertion of Inhibitory Neurotransmitters

In PD, it has been long observed that the subthalamic nucleus—the part of the brain targeted by deep brain stimulation, is overactive. This has become the focus of a gene therapy study at the University of California at San Francisco (UCSF), in which an inhibitory neurotransmitter is surgically inserted into the subthalamic nucleus to calm the activity in that area of the brain. This UCSF gene study was first done in experimental animals and then in a small group of PD patients in a phase 1 trial (safety study). Results were encouraging and participants showed significant improvement, which was maintained for a year. Although it appeared the treatment had helped, critics claimed that the improvement was due to a placebo effect. The study did, however, show that gene therapy was feasible and safe (Aminoff, 2010).

AADC Enzyme: Converting Levodopa to Dopamine

Other gene therapy trials have focused on an enzyme that converts levodopa to dopamine. Researchers have known that the effectiveness of dopamine-replacement diminishes after several years—not because the medication no longer works but because the substantia nigra is slowly losing its ability to make the enzyme that converts levodopa to dopamine. In a gene therapy study at UCSF (the second gene therapy study ever done for patients with Parkinson’s disease), researchers focused on an enzyme called aromatic acid decarboxylase (AADC), an enzyme that converts levodopa to dopamine.

This AADC study sought to restore the brain’s ability to convert levodopa to dopamine by inserting a gene containing the AADC enzyme into a virus, then injecting the virus into the brain of study participants. This was done in 10 patients with fairly severe PD who were good candidates for deep brain stimulation but elected instead to participate in the AADC clinical trial. Researchers used various scales to measure response to treatment, including the United Parkinson’s Disease Rating Scale (UPDRS), which showed approximately 30% improvement at 6 months. There was also an improvement in medication fluctuations—improved “on” times and reduced “off” times. Enzyme activity also appeared to increase (Aminoff, 2010).

Neurturin Gene Therapy

A third gene therapy technique using neurturin hopes to “rescue” sick dopaminergic nerve cells by injecting a growth/trophic factor. The goal is to help damaged nerve cells repair themselves. In this gene therapy study, the viral genes were removed and the genes to make neurturin were inserted. The altered virus was then injected into the brains of study participants. The phase 1 study involved 12 patients who were followed for 1 year. Over the course of a year their UPDRS showed significant improvement. Although the phase 1 trial seemed to improve the patient’s symptoms, researchers were unable to replicate the positive results in a larger, phase 2 study (Aminoff, 2010).