Genes With A Possible Role In Pd
Apart from the genes causing the six monogenic forms of PD, changes in a large number of additional genes were considered PD-causative and identified by linkage analysis or a candidate gene approach. Some of these genes even attained a PARKI designation . However, as discussed in the Genetic Classification of PD section, the link of some of these genes to PD is uncertain and not confirmed. Furthermore, mutations in some PARKs cause PD that is an inconsistent or only a minor feature of a more complex phenotype or are a very rare cause of PD . In addition, mutations in synphilin-1, NR4A2/Nurr1, POLG, mortalin, and recently presenilin-associated rhomboid-like protein were considered pathogenic based on the known function or expression/protein interaction pattern of the proteins they encode. Nevertheless, they too, are now recognized as only a minor contributor to the pool of genetic PD if at all.
Generating Relevant Neuronal Cell Types For Pd
The cellular reprogramming toolbox for researchers is rapidly expanding and includes a panoply of neuronal differentiation protocols to generate cells representing various brain regions. PD is a debilitating motor system disorder resulting from the selective degeneration of midbrain dopamine neurons located in the substantia nigra pars compacta. Protocols have been established to specifically generate dopaminergic neurons and brain cells with a midbrain molecular profile,.
How Environmental Factors Could Cause Parkinsons Disease
Scientists differ about the extent that brain cells are impacted by environmental factors. However, the statistics associated with the disease show that the environment can play a very large role in whether parkinsons disease develops.
Most often, it is exposure to toxic chemicals that could play a role in the development of Parkinsons disease. Usually, these combine with genetic factors to produce the conditions that cause Parkinsons.
Increasing scientific evidence suggests that Parkinsons may be caused by environmental factors such as exposure to herbicides such as Paraquat.
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How Hereditary Is It
If your mom or dad gets it, you might wonder if youll get it, too. The good news is that the chance of inheriting Parkinsons disease is rare . Just how hereditary Parkinsons disease is, depends on the exact mutation involved.
There are two categories of genetic factors linked. The first is causal, meaning the gene itself is capable of bringing on the disease.
One example of a causal link can be found in the SNCA gene. Researchers know of at least 30 mutations on this particular gene that can cause Parkinsons disease, especially in people younger than 50 years old.
The SNCA gene tells the body how to make a protein called alpha-synuclein. When the gene has a mutation, the body may produce too much alpha-synuclein or versions of the protein with an incorrect shape. Either of these problems can lead to alpha-synuclein to gather in the brain in clusters called Lewy bodies, which disrupt normal brain functioning. Lewy bodies are associated with Parkinsons, along with a range of other diseases .
Not all genetic mutations cause Parkinsons disease, though. Associated genetic factors increase a persons odds of developing the disease, but arent directly responsible for it.
Youre susceptible, but you need something else present as well , Dr Litvan says. That could be other genes or it could be an environmental factor.
There are many other genetic mutations that have been linked to Parkinsons, and ongoing research may continue to uncover other markers for the disease.
Who Should Get Genetic Testing
Two groups might consider getting genetic testing, according to Gilbert:
- People with Parkinsons who want to know if they have a mutation they may pass along to their children
- Children and siblings of family members with Parkinsons who want to determine their genetic risk for the disease
Right now its not standard of care for everyone with Parkinsons to get genetic testing, she says. The likelihood that were going to find one of these mutations that is known already is small, and even if you have a mutation associated with Parkinsons, it doesnt mean that youre going to get the disease.
So, at this point, the value of getting tested depends on the individual. Doctors can provide this type of genetic evaluation, or people may turn to direct-to-consumer genetic testing, such as 23andMe. These tests, however, can be limited.
You have to be careful with those panels because theyre not very comprehensive, says Gilbert. They may test for only one or two gene variations.
Currently, 23andMe analyzes DNA from spit samples for a variant in LRRK2 and a variant in the GBA gene associated with the disorder. The company makes it clear that the exam does not diagnose the disease, and there are many other mutations to consider.
Parkinsons patient Paul Cannon, PhD, who works for 23andMe as its Parkinsons research community manager, took the test and found that he had neither of the genetic variations.
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Who Should Consider A Genetic Test For Parkinsons
There are two groups of people who might consider getting genetic testing and we will discuss each group separately.
Genetic testing for PD is a common request and a number of commercial labs perform panels of genetic testing for PD. You may ask: How can I test myself for Parksinons? Whether youre considering getting a genetic test through your doctor, or performing one at home, its important to note that at-home test dont map the entire gene for mutations. Genetic testing through your doctor will test for GBA, PARK7, SNCA, LRRK2, parkin and PINK1.
Both groups are faced with two questions: Should I get genetic testing? And if so, what should I do with the results? Before we address these two questions, we need to learn more about the complexity of genetic testing in PD.
When Should A Person Seek Genetic Testing
Genetic testing is available for some genes related to Parkinsons disease, but testing may not provide useful information to individuals.
For one thing, a wide range of genes may play a role, and it is not possible to test them all. A person may also have a relevant feature but not go on to develop Parkinsons disease.
For example, only around 0.7% of people with symptoms of Parkinsons disease have changes in the LRRK2 gene, and around 0.3% have changes in the PRKN gene, according to a 2020 review.
Finding out in advance if a young person has the gene may help them prepare for the future if there is strong evidence of a family history of the condition. However, the results are unlikely to be conclusive and may cause unnecessary anxiety.
Anyone who is interested in genetic testing should discuss the pros and cons with a doctor and consider genetic counseling if they decide to go ahead.
The Parkinsons Foundation notes that testing is often hard to access. It can also be costly, and health insurance may not cover it. Genetic counseling can be an additional cost.
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Recessive And Dominant Genetic Conditions
Eye colour is, in reality, a little more complex than this, but some diseases work in this way. For instance, cystic fibrosis is a recessive genetic condition that only affects people if they inherit two copies of the faulty gene.
As we can see in the diagram, if a person has one faulty gene they are not affected but are a carrier.
Should a carrier have a child with another carrier that child would have a 1 in 4 chance of inheriting cystic fibrosis.
Family trees of those with recessive condition tend to have characteristic patterns based on these probabilities, but can be very complicated as it is hard to identify unaffected carriers.
Human diseases can also be caused by dominant genes. One example of this is Huntingtons where inheriting a single version of the faulty gene is sufficient to cause the condition. The pattern within a family tree left by dominant genetic traits or conditions is somewhat easier to identify at least half of all the children of someone with a dominant inherited condition, who has children with someone without the condition, will also have the condition.
Parkinsons Genes And Inheritance What We Know So Far
Parkinsons is an idiopathic condition, which means that it usually isnt connected to any particular cause. However, for a small minority, Parkinsons can be caused by inherited changes in genes. For other people, genetic variations can play a part in increasing the risk of the condition.
Its a complex and changing picture but, so far, changes in around 10 different genes have been linked to different effects on the risk of Parkinsons.
Lets take a closer look.
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What Genes Are Linked To Parkinson’s Disease
In 1997, we studied a large family that came from a small town in Southern Italy in which PD was inherited from parent to child . We found the gene that caused their inherited Parkinson’s Disease and it coded for a protein called alpha-synuclein. If one studies the brains of people with PD after they die, one can see tiny little accumulations of protein called Lewy Bodies . Research has shown that there is a large amount of alpha-synuclein protein in the Lewy Bodies of people who have non-inherited PD as well as in the brains of people who have inherited PD. This immediately told us that alpha-synuclein played an important role in all forms of PD and we are still doing a lot of research to better understand this role.
Currently, seven genes that cause some form of Parkinson’s disease have been identified. Mutations in three known genes called SNCA , UCHL1 , and LRRK2 and another mapped gene have been reported in families with dominant inheritance. Mutations in three known genes, PARK2, PARK7 , and PINK1 have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson’s disease . There is some research to suggest that these genes are also involved in early-onset Parkinson’s disease or in dominantly inherited Parkinson’s disease but it is too early yet to be certain.
Identification Of New Genes And Risk Factors For Pd
New PD-linked genes or PD risk factors can be identified by gene mapping or candidate gene approaches. Gene mapping in human diseases is the localization of genes underlying the clinical phenotypes of the disease on the basis of correlation with DNA variants , without the need for prior hypotheses about biological function. Genetic mapping methods include linkage analysis and genome-wide association studies. Alternatively, based on their known function, levels of expression, or mode of interaction , some genes can be considered plausible candidates, and as such, tested for in cohorts of patients.
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How Do Lrrk2 Gene Mutations Cause Parkinsons Disease
Healthy Individuals withoutLRRK2 Parkinsonâs disease
All humans have two copies of theLRRK2 gene which produce LRRK2 protein. In healthy people both copies of the gene are normal and therefore produce normal LRRK2 which regulates normal cellular biology.
Patients withLRRK2 Parkinsonâs disease
Patients withLRRK2 Parkinsonâs disease usually have one normal gene and one mutated gene. This means that patients produce both healthy LRRK2 protein and an overactive form of LRRK2 protein. The overactive LRRK2 is believed to drive neurodegeneration, causing Parkinsonâs disease, while the healthy LRRK2 continues to provide normal regulation to cells in other organs such as the lungs and kidneys.
Patients withLRRK2 Parkinsonâs disease â Non specific inhibition
In order to slow or stop the disease, ESCAPE Bio believes that overactive LRRK2 needs to be nearly fully inhibited. However, if healthy LRRK2 is also inhibited by the same amount then it may not be able to regulate cellular function in other organs, thereby driving histopathological changes in the lung and kidney, which are hard to detect and may be associated with irreversible pathology if they go unchecked.
Patients withLRRK2 Parkinsonâs disease â ESCAPEâs approach
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How Often Does Parkinsons Run In The Family
Most Parkinsons cases have no connection to a genetic cause, but scientists have found that some gene mutations can heighten an individuals risk. Researchers believe that a better understanding of these genes may improve ways of identifying and treating the illness.
The National Institute of Neurological Disorders and Stroke reports that an estimated 15 to 25 percent of people with Parkinsons have a family history of the disorder. The Michael J. Fox Foundation for Parkinsons Research estimates that about 10 percent of cases are linked with a genetic cause.
Parkinsons doesnt stand out as a hereditary disease over and above any other chronic diseases that people deal with, says Rebecca Gilbert, MD, PhD, chief scientific officer for the American Parkinson Disease Association in New York City. But if you have a parent with Parkinsons disease, you have about a fourfold greater risk over the general population.
Still, that risk is relatively small. About 1 percent of the population over 60 has Parkinsons, according to the Michael J. Fox Foundation, and that number rises to about 4 percent for those who have a mother or father with the illness, according to Dr. Gilbert. The overall message is: Just because you have a gene linked to Parkinsons does not mean you will get the disease.
People Who Already Have Pd: Should I Get Tested And What Do I Do With The Results
Up until recently, even people with PD with a very extensive family history of PD would not necessarily receive genetic testing because there were no clear uses for the results. There has been research directed at figuring out whether PD caused by or associated with certain mutations have particular clinical characteristics . However, there remains so much variability in clinical characteristics even among people with the same PD mutation, that there are still no clear practical implications in knowing whether a PD patient harbors a particular mutation. There is also, so far, no difference in treatment or management of PD whether or not the patient harbors one of the known mutations. That may change however, with the advent of clinical trials that target particular mutations.
There are two genes that have received particular attention recently because medications are being developed that target those with mutations of these genes.
GBAis a gene that increases the risk of developing PD. The gene encodes for the GBA enzyme, a protein used by the body to break down cellular products. Having two abnormal GBA genes causes Gauchers disease, which is characterized by the buildup of these cellular products resulting in fatigue, bone pain, easy bleeding and an enlarged spleen and liver. When a person inherits only one abnormal gene, he or she does not develop Gauchers disease, but does incur a small increased risk of PD. Most people with one mutated GBA gene do not develop PD.
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What Role Do Genes Play
Your genes are like your body’s instruction book. So if you get a change in one of them, it can make your body work in a slightly different way. Sometimes, that means you’re more likely to get a certain disease.
There are several genetic mutations that can raise your risk for Parkinson’s, each by a little bit. They have a part in about 1 in 10 cases.
If you have one or more of these changes, it doesn’t mean you’ll get Parkinson’s. Some people will, but many won’t, and doctors don’t know why. It may have to do with other genes or something in your environment.
Reasons Why Parkinsons Disease Occurs
The scientific reason given for Parkinsons disease is that the patient has lost nerve cells in the part of the brain called the substantia nigra. A very important chemical called dopamine is produced by the substantia nigra. The loss of the ability to produce dopamine contributes to the early stages of Parkinsons disease.
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What Is Parkinson Disease
Parkinson disease is a movement disorder. It can cause the muscles to tighten and become rigid This makes it hard to walk and do other daily activities. People with Parkinsons disease also have tremors and may develop cognitive problems, including memory loss and dementia.
Parkinson disease is most common in people who are older than 50. The average age at which it occurs is 60. But some younger people may also get Parkinson disease. When it affects someone younger than age 50, it’s called early-onset Parkinson disease. You may be more likely to get early-onset Parkinson disease if someone in your family has it. The older you are, the greater your risk of developing Parkinson disease. It’s also much more common in men than in women.
Parkinson disease is a chronic and progressive disease. It doesn’t go away and continues to get worse over time.
What Are The Methods Of Preventing Parkinsons Disease
As said earlier the concrete causes of Parkinsons disease are yet to be discovered. Thus, specific prevention techniques are not known as of now. However, based on few researches, some methods of prevention have seemed beneficial. They include-
Tea: Intake of caffeine and green tea may help lower the risk of developing Parkinsons disease.
Exercise: Exercise and a healthy and balanced diet keeps all form of diseases including Parkinsons at bay.
Mediterranean Food: According to few studies following a Mediterranean diet including fish, vegetables, fruits, olive oil, whole grains, nuts and seeds may lower the risk of getting Parkinsons disease.
Meat: It is important to limit dairy and red meat consumption in order to avoid Parkinsons.
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