Scientists Locate Parkinson’s Gene
BETHESDA, Md. – For the first time, scientists have pinpointed the location of a gene they believe is responsible for some cases of Parkinson’s disease. Their discovery provides strong evidence that a genetic alteration is capable of causing the disease. The study, published in the November 15 issue of Science, sheds light on the mysterious origins of this devastating neurological disease that affects at least 500,000 Americans.
The findings are reported by National Institutes of Health scientists from the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke , in collaboration with researchers from the UMDNJ-Robert Wood Johnson Medical School in New Brunswick, New Jersey, and the Istituto de Scienze Neurologiche in Naples, Italy.
“This exciting result gives us a powerful new tool to understand why nerve cells die in Parkinson’s disease and how to stop them from dying. It will usher in a new era of Parkinson’s disease research,” said NINDS Director Zach Hall, Ph.D.
Efforts to locate the gene intensified after an August 1995 NIH-sponsored workshop on Parkinson’s disease at which scientists from NHGRI and NINDS met Roger Duvoisin, M.D., of UMDNJ-Robert Wood Johnson Medical School. Soon after, the NIH scientists, led by Mihael Polymeropoulos, M.D., of NHGRI, began to carry out a genetic analysis of Parkinson’s disease using DNA from patients identified and followed by an international team led by Dr. Duvoisin.
Gene Therapy For Parkinsons Disease
You may have read about efforts to use gene therapy as a treatment for Parkinsons disease . Its an exciting prospect and studies are underway, with some positive results so far. Understanding these studies and therapies requires some background information about what genes are and how they work, so Ive included a glossary at the end of this article. You might find it helpful to scroll down and get familiar with the terminology before reading the rest of the article.
How Hereditary Is Parkinson’s Disease
If your mom or dad gets Parkinson’s disease, you might wonder if you’ll get it, too. The good news is that the chance of inheriting Parkinson’s disease is rare . Just how hereditary Parkinson’s disease is depends on the exact mutation involved.
There are two categories of genetic factors linked to Parkinson’s. The first is “causal,” meaning the gene itself is capable of bringing on the disease.
One example of a causal link to Parkinson’s disease can be found in the SNCA gene. Researchers know of at least 30 mutations on this particular gene that can cause Parkinson’s 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 Parkinson’s, along with a range of other diseases .
Not all genetic mutations cause Parkinson’s disease, though. “Associated” genetic factors for Parkinson’s increase a person’s odds of developing the disease, but aren’t directly responsible for it.
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“You’re susceptible, but you need something else present as well ,” Dr. Litvan says. “That could be other genes or it could be an environmental factor.”
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Ropad Study Of Parkinsons Genetics Enrolling 2500 More Patients
However, many of the GWAS signals are often found in genomic regions outside genes, or the segments of DNA that carry instructions for proteins thus, few have been implicated in specific biological mechanisms.
Although recent GWAS has seen great strides in identifying risk associated with , the functional significance of these associations remains elusive, the researchers wrote.
Given that, a team of researchers at the Hunan University of Chinese Medicine, in China, now turned to another approach, called a transcriptome-wide association study or TWAS. This approach investigates the relationship between disease risk and gene expression gene activity which is directly tied to protein production and biological function.
Using TWAS gene activity data from 13 different brain tissue samples, the researchers sought to identify gene candidates that may directly be involved in susceptibility to Parkinsons.
The team included data from 15,056 Parkinsons cases and 449,056 people without the condition , as well as 18,618 UK Biobank proxy cases, which are individuals who do not have Parkinsons but have a first-degree relative a parent, sibling, or child who does.
A total of 18 genes were found whose expression was significantly associated with Parkinsons. The most significant gene, called LRRC37A2, was associated in all 13 brain tissues, including the hypothalamus and basal ganglia, an area that contains nerve cells affected by the disorder.
Studies Of Pd With Patient
The discovery of iPSC technology,, has offered the capacity to generate live brain tissue from healthy subjects and patients for studying neurodegenerative diseases. Directed reprogramming and neuronal differentiation of iPSCs allows the study of specific neuronal subtypes. Human-derived neurons offer a unique opportunity for modeling real cases of human genetic diseases in vitro. The ability to generate neurons both from PD patients and healthy control individuals allows the identification of early disease-linked phenotypes and provides a new paradigm for preclinical drug development and validation .
Fig. 3: Using brain cells generated from patient-derived iPSC to study PD in vitro.
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Human Ipsc Studies Of Pd Highlight Converging Molecular And Cellular Pathways Across Genetic Subgroups
Our analysis of 385 iPSC-derived cell lines from 67 published studies reveals that many PD neuronal phenotypes are shared between genetically heterogeneous familial and sporadic patients . Notably, impairments in mechanisms involved in cellular waste recycling, mitochondrial function, neuronal morphology and physiology, and sensitivity to reactive oxygen species are most common across patient lines with varying genetic predispositions . The studies measured cellular phenotypes that occurred either spontaneously or in response to chemicals mimicking cellular aging and stress . It is important to note that the frequency of reported phenotypes in our meta-analysis may be biased because only few studies reported negative results ,,,,,,,,,,,,. In addition, most cell lines were not systematically phenotyped without prior hypothesis and thus, there is likely to be an ascertain bias in these phenotypes. Less hypothesis-driven multimodal or omics analysis will help to address such bias,,,,,,,,. Phenotypes caused by genomic predispositions allude to crosstalk and impairments in multiple pathways that act collectively to mediate selective degeneration of dopaminergic neurons in the substantia nigra and will be discussed in detail below.
Fig. 4: Phenotypic insights from iPSC studies of Parkinsons disease.
Genetic Principles And Exceptions Thereof In Familial Pd
The majority of PD cases are sporadic, i.e., only about 10% of patients report a positive family history . Out of the six genes unequivocally linked to heritable, monogenic PD, mutations in SNCA , and LRRK2 are responsible for autosomal-dominant PD forms, and mutations in Parkin , PINK1 , DJ-1 , and ATP13A2 are accountable for PD that displays an autosomal recessive mode of inheritance.
In general, the inheritance patterns of human disorders are identified by examining the way the disorders are transmitted in the family of the index patient. Such a pedigree analysis requires a careful assembly of the disease records of the family members over several generations, and if possible, examination and sample collection from affected and unaffected individuals from the pedigree. All of the currently known monogenic PD forms are autosomal , which means that they are linked with regions on autosomes .
Pedigree of a PD family that comprises affected members with and without the LRRK2 p.G2019S mutation. Five mutation carriers are unaffected, showing reduced penetrance, two mutation carriers are affected with dystonia, showing variable expressivity, and one affected family member does not have the p.G2019S mutation in LRRK2. Black symbols – affected individuals white symbols – unaffected individuals half-filled symbols – individuals with dystonia + – mutation carriers.
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Faqs: Genetics & Parkinsons
If I have Parkinson’s disease will my child get it too? Will I inherit Parkinson’s if my parent or grandparent has it?
Most people with Parkinson’s have no known genetic link. Their children will likely never develop Parkinson’s. There are some known genetic variations that increase the risk of getting Parkinson’s, but most people with these variations do not get Parkinson’s. Like many other diseases, Parkinson’s is a result of a complex interaction between genes and environmental factors.
In a small number of people , Parkinson’s is inherited and can affect multiple family members. Their children may have a higher risk of developing Parkinson’s. However, there is no guarantee they will develop PD.
What if my genetic test is positive for a Parkinson’s gene?
Scientists have identified several genetic mutations that can increase the risk of developing Parkinson’s. If someone tests positive for a mutation in a Parkinson’s gene, it does not necessarily mean they will develop PD. Some people who have mutations in the genes associated with Parkinson’s never develop PD. A person may inherit a hereditary genetic mutation that increases their risk for Parkinson’s however, they may also inherit other genes, be exposed to environmental factors or have lifestyle choices that offset the risk. Genetic testing is currently available for the following genes related to Parkinson’s: GBA, PARK7, SNCA, LRRK2, parkin and PINK1.
What can I do with my genetic test results?
Genetics And Parkinsons Disease
The symptoms of Parkinsons disease appear to occur when the brain is no longer able to produce enough dopamine. Low dopamine levels in the brain can affect movement. It is not yet clear what role genetic factors may play in this process.
However, experts have identified specific genes in which changes appear to increase the risk of developing Parkinsons disease. The symptoms a person experiences may depend on their specific genetic changes.
Genetic changes can affect how mitochondria work. Mitochondria are the parts of a cell that produce energy. As they do this, they release byproducts commonly known as free radicals. Free radicals can cause cell damage.
Usually, cells can counter free radicals, but genetic changes can stop this from happening, and the free radicals can cause damage to dopamine cells.
Genetic changes can also lead to accumulations of a protein called alpha-synuclein in and around neurons throughout the brain. These accumulations are known as Lewy bodies, and the damage they cause can result in Lewy body dementia, which has links to Parkinsons disease.
Dopamine-producing nerve cells appear to be particularly susceptible to Lewy bodies, and some people develop both Parkinsons disease and Lewy body dementia.
Specific gene changes have specific outcomes. For example, SNCA affects the processing of alpha-synuclein, and PRKN impacts how mitochondria work.
The genetic changes involved in Parkinsons disease can be:
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Can I Be Tested
Tests are generally arranged through a healthcare professional who can then interpret the results and give advice on how the information can be used.
Genetic testing is now also available from a number of companies who deal directly with people being tested. This can have several implications:
- Your doctor is not automatically informed of results, allowing you to keep findings to yourself if you wish.
- Results will not automatically be passed to your insurance company, although you should check your policy as you may be required to reveal all genetic test information. Failure to do so could invalidate your cover.
- You may not get the opportunity to discuss your test results and their implications with an experienced healthcare professional.
Important! Thoroughly check the credentials of any company offering genetic testing, as not all provide a high standard of service.
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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Other Factors Influencing Parkinson’s Disease Risk
Other factors besides genetics can influence someone’s chances of developing Parkinson’s disease, including:
- Age: The risk of developing Parkinson’s disease increases as a person ages.
- Sex: Males have a higher chance of developing Parkinson’s disease than females.
- Family history: First-degree relatives of an individual with Parkinson’s disease have a higher chance of developing Parkinson’s disease.
- Exposure to certain chemicals increases the risk of developing Parkinson’s disease.
Gene4pd: An Integrative Genetic Database And Analytic Platform For Parkinsons Disease
Figure 4. Snapshot of search panel and variant-level implications in Gene4PD. Snapshot of search panel in Gene4PD. Quick search panel and advanced search panel in Gene4PD are illustrated. Snapshot of variant-level implications in Gene4PD. Six sections including Summary,Rare variant,Associated SNPs,CNVs,Differential expression gene,Differential DNA methylation, are set in variant-level implication.
One of the main advantages of Gene4PD is that it provides an interface for analyzing genetic data according to the specific needs of the user . The analysis process includes four simple steps of filling in an email address, choosing the Trio or Non-trio option of the genetic data, uploading genetic data files , and inputting basic information of samples. Gene4PD will then analyze the rare damaging variants using default parameters. Importantly, Gene4PD also supports a flexible control panel so that users can conveniently adjust the values of quality control, data sources of annotation, and parameters for identifying rare damaging variants. The annotation section contains four sub-panels: Basic information annotation, Pathogenicity prediction of missense variants, Allele frequency in variant population, and Clinical-related database. When the analysis is complete, Gene4PD will send a link to the user by email for downloading the results.
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Gene Therapy For Parkinson Disease Demonstrates Safety Improved Motor Function
From baseline, all participants showed improvements on CGI-Improvement scale scores while all but 1 patient demonstrated improvement on modified Hoehn and Yahr scores.
This content originally appeared on our sister site, NeurologyLive.
The gene therapy VY-AADC01 , provides long-term safety and durability in patients with Parkinson disease , according to newly published 36-month findings from the phase 1 PD-1101 study .
The study, conducted by lead author Chadwick Christine, MD, neurologist, Parkinsons Disease and Movement Disorders Clinic, UCSF Health, and colleagues, found that a single administration of the therapy was well-tolerated and resulted in stable or improved motor function and quality of life across cohorts.
Christine and colleagues assessed safety and tolerability of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic L-amino acid decarboxylase enzyme in 15 patients aged 40 to 70 years with moderately advanced PD. The treatment was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts, with 5 participants each.
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Patients in cohort 1 and 2 also showed improvements in PD diary good ON time, with increases from baseline at the final 36-month follow-up of 2.1 hours and 2.2 hours , respectively. Those in cohort 3 demonstrated improvement in good ON time at 12 months that returned to baseline at both the 24- and 36-month mark.
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Gene Therapy And Parkinson’s
Although it is widely agreed that Parkinsons is not usually inherited through the genes our parents pass on, researchers believe that gene therapy will one day be able to prevent the death of dopamine-producing cells in the brain and help to revitalise dying cells in the early stages of the disease. This is important as current treatments tend to become less effective over time and only control symptoms they do not slow or halt the progression of Parkinsons. Gene therapy has the potential to alter the way neurons in the brain work.
The aim of current research is to be able to deliver specific genes directly into neurons in the affected area of the brain. Three gene therapy approaches have already entered clinical testing:
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Why Genetic Testing For Parkinsons Disease Is Complex:
- There are many genes that are associated with the development of PD. This list continues to grow as more genes are discovered. Testing of only some of these genes is available in commercial labs.
- The majority of people with PD, even those with a family history of PD, do not harbor one of these identified abnormal genes. The genetic contribution to PD in these people is yet to be discovered.
- For a particular gene there may be a number of different mutations associated with disease, some of which are more common than others. Commercial testing may identify only the most common of the mutations, and therefore not capture everyone who carries a disease-causing mutation.
- Conversely, only particular mutations in a gene may be associated with disease. Commercial testing may identify changes in a gene that may not have clinical consequences. This can be confusing for patients who even after genetic testing may not know whether they harbor a disease-causing mutation.
- Different mutations can be enriched in different ethnic populations. For example, Ashkenazi Jews and North African Berbers have an increased risk of carrying Leucine rich repeat kinase 2 mutations. Glucocerebrosidase mutation frequency also varies greatly with ethnicity and is also increased among Ashkenazi Jews.
In addition to the above, it is important to realize that not all genes associated with PD contribute to disease in the same way: