Parkinson’s Disease Genetics: Laying The Foundation For Genetic
Over the last two decades, genetic studies have revolutionized our understanding of the etiology of PD.810 Initially believed to be a pure sporadic disease, Parkinson’s is now widely accepted to have a substantial genetic component.11 The -synuclein gene was the first to be unequivocally associated with PD.12 Although monogenic, inherited forms of PD are rare and constitute around 5%10% of all cases, 20% of patients with PD report having one affected first or second-degree relative.9 The initial discoveries of -synuclein gene point mutations and multiplications as a cause of PD were followed by the identification of numerous genes linked to PD pathogenesis. Since then, many other genes have been associated with PD, either as causative genes and/or risk factors for developing the disease.10
Initial studies identified rare disease-causing genetic variants through linkage analysis in large families with PD. The advent of higher throughput methods such as next-generation sequencing techniques and increased worldwide collaborations has led to the identification of common genetic components of PD using genome-wide association studies . To date, at least 90 independent risk signals have been identified from 7.8 million single nucleotide polymorphisms evaluated in more than 37,000 patients, 17,000 proxy cases , and 1.4 million controls.13,14
Antibiotics And Neuroinflammation In Parkinson’s Disease
Recent evidence suggests that inflammation seems to play a crucial role in the etiology of PD . In evidence, once activated, microglial cells produce and release proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 that contribute to cell damage and neuronal death . The regulation of inflammation, therefore, may be useful to prevent the development and progression of PD. In this respect, antibiotics constitute a promising strategy to protect neurons from inflammation-induced degeneration .
Immunosuppressive properties of rifampicin have been known since the 1970s . Bi et al. found that rifampicin blocked the release of proinflammatory mediators such as nitric oxide, prostaglandin E2, TNF-alpha, and IL-1 beta from lipopolysaccharide-stimulated BV2 microglial cells. These antiinflammatory effects seem to be associated with the inhibition of neurotrophic factor-kappa B, mitogen-activated protein kinases , and toll-like receptor-2 and receptor-4 molecules, which are essential for the secretion of proinflammatory mediators .
Ceftriaxone also presents antiinflammatory effects. Chu et al. found this antibiotic reduces the expression of metalloproteinase type 9 and TNF-alpha. Besides that, its neuroprotective properties seem to depend in part on inhibitory effects of microglial activation .
Figure 29.4. Astrocytic reaction in substantia nigra pars compacta.
Figure 29.5. Neuroprotective mechanism of doxycycline.
S. Pablo Sardi, Marco A.S. Baptista, in, 2021
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.
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Parkinson Disease 24 Autosomal Dominant Susceptibility To Park24
Phenotype-Gene Relationships
NEUROLOGIC MISCELLANEOUS MOLECULAR BASIS
â¼TEXT
A number sign is used with this entry because of evidence that susceptibility to autosomal dominant Parkinson disease-24 is conferred by heterozygous variation in the saposin D domain of the PSAP gene on chromosome 10q22.
â¼Description
Parkinson disease-24 is an autosomal dominant disorder characterized by classic Parkinson disease features, including adult onset, asymmetric limb involvement initially, and slowly progressive motor dysfunction. PARK24 shows incomplete penetrance, consistent with the presence of the PSAP mutation being a susceptibility factor for development of the disease .
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see .
â¼Clinical Features
reported 3 unrelated Japanese families segregating autosomal dominant adult-onset Parkinson disease. There were 8 affected individuals, 2 of whom had died without genetic material available for study. The remaining 6 patients presented between 33 and 60 years of age with classic features of the disorder, including asymmetric involvement at onset, resting tremor, and initial good response to dopaminergic therapy. There were 2 sibs in family 2 who carried the PSAP mutation and presented with extrapyramidal signs such as tremor and muscular rigidity, but they were not clearly diagnosed with Parkinson disease.
â¼Inheritance
â¼Molecular Genetics
â¼Animal Model
â¼REFERENCES
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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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Glucocerebrosidase Gene Mutations And Parkinson Disease Objectives
Stuart K. Shapira, M.D., Ph.D.National Center on Birth Defects and Developmental DisabilitiesCenters for Disease Control and Prevention
Educational objectives
After reading this case study, you should be able to
- Identify inconsistencies between study and control populations which might bias the results of gene-disease association studies.
- Calculate gene-disease associations in terms of absolute, relative, and attributable risks.
- Assess the public health implications of the risk for developing Parkinson Disease for the Ashkenazi Jewish population, based on the findings.
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.
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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.
Causal And Associated Genes
The idea that a gene abnormality may cause some cases of Parkinsons dates back to 1997. At that time, scientists at the National Human Genome Research Institute and the National Institutes of Health first precisely identified that an irregularity in the synuclein alpha gene , the gene that provides instructions to make the protein alpha-synuclein, could lead to this movement disorder.
Alpha-synuclein is found in abundance in the brain and is thought to help regulate the release of dopamine, a chemical involved in the transmission of signals between nerve cells . With Parkinsons, the brain doesnt produce enough dopamine. This 1997 research on SNCA confirmed that at least one form of Parkinsons disease is inherited.
Up until 1997, people did not broadly think that Parkinsons could be hereditary or familial, says James Beck, PhD, chief scientific officer with the Parkinsons Foundation. With that discovery, we began to identify a number of genes linked with Parkinsons.
In 2004, scientists discovered the most common genetic contributor to Parkinsons, a mutation in LRRK2, a gene that is active in the brain and pushes a persons risk to 30 percent. Certain ethnic groups are more likely to have this gene irregularity. The faulty LRRK2 gene accounts for 1 percent to 2 percent of all Parkinsons cases, according to a review published in February 2016 in Biochemical Journal.
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Should I Get Tested For Genetic Markers For Parkinson’s
You can find out if you have certain genetic markers for Parkinson’s disease with at-home genetic tests. However, Dr. Litvan is cautious about recommending genetic testing for everyone. Remember: Most people with the mutations linked to Parkinson’s never get the disease, so you may end up with a ton of unnecessary stress and worry if your results reveal one of these genetic factors.
Role Of Heterozygous Mutations In Recessive Pd Genes
A pathogenic effect of certain heterozygous mutations in parkin and PINK1 has been postulated,- complicating the genetic counseling of these individuals. A number of theories have been put forward as to why a heterozygous mutation in these genes might cause PD: A second pathogenic mutation might escape detection by the standard screening methods second, it is possible that some mutations are dominant and cause disease in the heterozygous state, or a heterozygous mutation may contribute to disease development as a genetic risk factor. However, a recent study did not find a significant difference in heterozygous parkin mutations in cases and controls. Furthermore, another study found that 10% of cases with a heterozygous parkin mutation had pathogenic homozygous mutations in other recessive PD genes, emphasizing the importance of comprehensive screening of these individuals.
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Autosomal Dominant Genetic Features
People have two copies of each gene. In autosomal dominant inheritance, a child can inherit either a healthy gene or one that is not working correctly. They will have a 50% chance of inheriting a faulty gene.
Autosomal dominant genes that have associated with Parkinsons disease include:
- SNCA, or PARK1
- DJ-1
- PRKN
It is important to note that inheriting any of the genes that scientists have identified as being related to Parkinsons disease does not necessarily mean that a person will develop the condition.
Diagnostic Features Of Pd
The cardinal pathologic feature of PD is the loss of dopaminergic neurons in the substantia nigra with intracytoplasmic inclusions in the remaining, intact nigral neurons., Symptoms of PD typically onset when 5080% of the dopaminergic neurons in the substantia nigra are no longer functioning. Traditionally, the presence of Lewy bodies was required for pathologic confirmation of PD however, it has been recognized recently that nigral pathology may occur in the absence of Lewy bodies.
Several other neurologic entities must be considered as part of the differential diagnosis of PD. They include parkinsonism-predominant multiple system atrophy , progressive supranuclear palsy, corticobasal degeneration, essential tremor, drug-induced parkinsonism, postencephalitic conditions, Lewy body dementia, and AD. Parkinsonism can also be a prominent feature of some Mendelian disorders, including spinocerebellar ataxias , Huntington disease, dopa-responsive dystonia, familial prion disease, frontotemporal dementia with parkinsonism-17, Wilson disease, and X-linked dystonia-parkinsonism syndrome . Laboratory or radiologic studies cannot be used to confirm PD however, they are useful in excluding alternative diagnoses, such as stroke, tumor, and thyroid disease.
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Eukaryotic Translation Initiation Factor 4 Gamma 1
Mutations in eukaryotic translation initiation factor 4 gamma 1 were recently proposed as the cause of autosomal dominant PD in a kindred with LB pathology. However, subsequent studies have not been able to convincingly replicate this finding and have identified reportedly pathogenic variants in controls.-
Genes Linked To Parkinsons Disease
Theres a long list of genes known to contribute to Parkinsons, and there may be many more yet to be discovered. Here are some of the main players:
SNCA: SNCA makes the protein alpha-synuclein. In brain cells of individuals with Parkinsons disease, this protein gathers in clumps called Lewy bodies. Mutations in the SNCA gene occur in early-onset Parkinsons disease.
PARK2: The PARK2 gene makes the protein parkin, which normally helps cells break down and recycle proteins.
PARK7: Mutations in this gene cause a rare form of early-onset Parkinsons disease. The PARK7 gene makes the protein DJ-1, which protects against mitochondrial stress.
PINK1: The protein made by PINK1 is a protein kinase that protects mitochondria from stress. PINK1 mutations occur in early-onset Parkinsons disease.
LRRK2: The protein made by LRRK2 is also a protein kinase. Mutations in the LRRK2 gene have been linked to late-onset Parkinsons disease.
Among inherited cases of Parkinsons, the inheritance patterns differ depending on the genes involved. If the LRRK2 or SNCA genes are involved, Parkinsons is likely inherited from just one parent. Thats called an autosomal dominant pattern, which is when you only need one copy of a gene to be altered for the disorder to happen.
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Pags Presented Specific Expression Patterns
To investigate the tissue specificity of PAGs, we calculated the preferential expression of tissues of each gene and systematically tested the enrichment of preferential expression of tissues of the 107 PAGs using expression data derived from the GTEx project. As a result, we found that the 107 PAGs were significantly expressed in 12 tissues , all of which belong to the brain, including the substantia nigra, hippocampus, amygdala, spinal cord, frontal cortex, hypothalamus, putamen, anterior cingulate cortex, caudate, nucleus accumbens, and cerebellum . This result provides novel evidence that PAGs are likely involved in the other brain specific gene regulation, as well as the known brain-specific gene regulation.
Figure 1. Distribution of the preferential expression tissue of the Parkinsons disease-associated genes. Tissues with top 50% expression levels were defined the preferential expression tissue. The average expression level in 53 tissues were sourced. P-values were calculated by Fishers test.
Figure 2. Heat map of normalized expression levels of Parkinsons disease-associated genes in 45 types of inhibitory neurons and 24 types of excitatory neurons. Only Parkinsons disease-associated genes showing different expression levels between inhibitory and excitatory neurons are shown P-values were calculated by the Wilcoxon rank sum test.
Assessment Of Family History
The majority of our identified studies use self reporting or self administered questionnaires to assess family history of PD. Categorising PD cases who have relatives with isolated tremor as having a positive family history, can significantly increase the number of familial cases, especially among early onset PD cases.
Performing individual examinations may increase the precision with which a diagnosis of PD is made in relatives of cases and controls, rather than reliance on patient reporting of diagnoses or symptoms such as tremor. It has also been shown that significant numbers of previously unrecognised PD patients can be identified by examination despite a negative family history. It can often however be difficult verifying familial diagnoses in diseases affecting the elderly as relatives are often deceased and not subjected to postmortem examination. Subclinical Parkinson’s disease, diagnosed on the basis of Lewy body pathology in people without prior symptoms of PD, is observed in up to 10% of individuals subjected to postmortem neuropathological examination. No study includes pathological examination of all relatives of both cases and controls, which currently represents the gold standard in diagnosing PD.
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