http://www.sciencedaily.com/releases/2007/07/070726085925.htm
ScienceDaily (July 27, 2007) — The scientist who discovered “Sly Syndrome” nearly four decades ago and a team of colleagues at Saint Louis University are a step closer to finding an approach to treat the rare genetic disease. Sly Syndrome causes bone defects, mental retardation, vision and hearing problems, heart disease and premature death.
They found that a potentially life-saving enzyme can be induced to cross the blood-brain barrier, a structure which protects the brain from foreign substances, if it is given with the hormone epinephrine.
Ever since William S. Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University, discovered the rare genetic disease in 1969, he and his colleagues have conducted research to learn more about how to treat it.
He says their recent findings have significance beyond treating the extremely rare disease that bears his name.
“There are at most 100 living cases of Sly Syndrome. Nonetheless, this disease is a model for all the diseases in this group, some of which are much more common,” Sly says.
“Lysosomal storage diseases affect 1 in 7,000 live births, and 90 percent of those with the diseases have brain involvement. What we find with Sly Syndrome has some importance for all those diseases as well. It is potentially a big finding and an important first step.”
The discovery potentially points to a new way to get big molecules, such as certain medications, across the blood-brain barrier. It is reported in the Proceedings of the National Academy of Sciences online early edition the week of July 16.
SLU researchers found that the right amount of epinephrine probably works by stimulating transport by vesicles — blister-like wrappers that carry substances across the blood-brain barrier – so that the enzyme missing in patients who have Sly Syndrome can get into the brain.
Those who have Sly Syndrome lack the enzyme called beta-glucuronidase. Without this enzyme, protein-sugar molecules accumulate in the brain and other organs in the body. By replacing the missing enzyme, doctors believe they can treat the genetic disease.
The problem, though, was slipping the enzyme past the blood-brain barrier to where it needs to do its work.
“This is a disease that is simply made for testing drug delivery vehicles. If you can get the enzyme into the brain, the vehicle that delivered it could work to deliver other chemicals, too,” says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological sciences at Saint Louis University, and a leading researcher on the blood-brain barrier.
Sly Syndrome, which occurs in fewer than one in 100,000 births, is a progressive disorder that ranges in severity from mild to deadly. It is among a group of genetic diseases call mucopolysaccharidoses.
“Some children who have this group of diseases are doomed to an early death because they don’t make a certain enzyme,” Banks says.
Enzyme replacement therapy — or putting the missing enzyme into the bodies of those who have Sly Syndrome — holds promise in treating the physical problems of the disease.
“In the case of Sly Syndrome, the missing enzyme is more than 1,000 larger than a sugar molecule and so huge it can’t get across the blood-brain barrier, which prevents it from reaching the brain.”
Scientists used a mouse model to figure out how to get the enzyme into the brain. They knew that injections of the missing enzyme into the brains of baby mice reached their target, but similar injections into mature mice did not. As the mice grew older, the transporter that brought the enzyme past the protective blood-brain barrier was lost.
“We found that the right amount of epinephrine allowed the enzyme to pass into the brain of older mice, which means we reinduced the way to get the enzyme where it is needed,” Banks says.
Epinephrine is a drug that treats cardiac arrest and is given to open the airways of asthma patients who have difficulty breathing. Discovering epinephrine as the transportation key to unlock the blood-brain barrier for the missing enzyme was “a shot in the dark,” Banks says.
”High doses of epinephrine can destroy the blood brain barrier and let everything into the brain, which is toxic,” Banks says. “We tested three things. One didn’t work at all. One worked partially and epinephrine worked incredibly well.”
The finding changes how scientists look at getting medications through the blood-brain barrier, he says, and could have implications for treating other diseases such as Alzheimer’s disease and obesity.
Instead of viewing the blood-brain barrier as an obstacle to fight, researchers should consider it something to finesse, using its special features to help in drug delivery, Banks adds.
“The field has approached the problem as if you have a Volkswagen that can get across the street and you put your cargo on it so the cargo can get there too. We’ve found that trying to transport the cargo changes the Volkswagen and the Volkswagen can no longer get across.”
The research was funded by the National Institutes of Health, The Sanfilippo Syndrome Medical Research Foundation and VA Merit Review.
http://rarediseases.info.nih.gov/TRND/
The need and opportunity for Therapeutics for Rare and Neglected Diseases (TRND) are enormous. Of the 7,000 human diseases, fewer than 300 are of interest to the biopharmaceutical industry, due to limited prevalence and/or commercial potential. More than 6,000 of these diseases are rare (defined by the Orphan Drug Act as <200,000 U.S. prevalence), and the remainder are neglected because they affect impoverished or disenfranchised populations. Researchers have now defined the genetic basis of more than 2,000 rare diseases and identified potential drug targets for many rare and neglected diseases (RND).
TRND received $24 million in the National Institutes of Health (NIH) budget for fiscal year 2009. TRND is a collaborative drug discovery and development program with governance and oversight provided by the Office of Rare Diseases Research (ORDR). Program operations will be within the intramural research program adjacent to the NIH Chemical Genomics Center (NCGC) and will be administered by the National Human Genome Research Institute (NHGRI).
Frequently Asked Questions
TRND (PDF – 30)
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Neglected Diseases (PDF – 36KB)
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TRND Press Release (PDF – 80KB)
http://news.smh.com.au/breaking-news-national/cell-malfunction-linked-to-many-diseases-20090521-bfv7.html
The tiny “recycling unit” at the core of every human cell can fail, and research is increasingly placing this malfunction at the root of a host of common deadly illnesses.
Alzheimer’s disease, stroke, heart disease and certain cancers can all be linked to a dysfunction of the lysosome, says South Australian biochemical geneticist Professor John Hopwood.
“You might think these lysosomal diseases are uncommon but in fact we’ve been studying the tip of an iceberg,” Prof Hopwood says.
“The more we study these disorders … it turns out the lysosome has a big role to play in many illnesses that the community has.”
Lysosomal disease is a process which sees affected human cells lose their ability to create new versions of themselves, instead becoming clogged as genetic “material gets into the recycler but can’t get out”, Prof Hopwood explains.
His team at Adelaide’s Women’s and Children’s Hospital led the development of world-first treatments for two rare lysosomal diseases – Maroteaux-Lamy and Hunter syndromes.
These and other Lysosomal disease occur in one in every thousand children and it results in developmental delays, bone deformities, heart and breathing difficulties, behavioural problems and a shortened life span.
Prof Hopwood has also developed a test able to highlight these genetic conditions in newborns, allowing treatment to get underway before irreversible features develop.
While his work has focused on treating children with these rare conditions, Prof Hopwood says the field’s future would also go to unearthing the links between lysosomal disorders and common diseases.
In the brain, the disorder was known to lead to the loss of brain matter which, over time, could manifest as Alzheimer’s or dementia.
“Where you have heart failure because a valve doesn’t function properly, it may be due to poor signalling by control systems that are influenced by these lysosomal storage disease problems,” Prof Hopwood says.
“So these rare diseases give us an insight into the ‘berg’ part of the ‘iceberg’, which is affecting the majority of us.
“And if we can understand how it contributes then we can reduce the impact of all of these disorders in the community.”
The Australian Academy of Technological Sciences and Engineering (ATSE) paid tribute to Prof Hopwood for his 25 years work in the field at a gala event in Sydney on Wednesday night.
He was announced as one of the recipients of a 2009 ATSE Clunies Ross Award, which recognises the nation’s pre-eminent scientists who have bridged the gap between research and the marketplace.
Today is an INCREDIBLE day in the world of Gaucher’s Disease! Two very important studies came out in the past day or two that have not only proven the strong link between Parkinson’s Disease and Gaucher’s Disease, but they will also open the eyes of many Parkinson researchers and biopharmaceuticals towards Gaucher’s Disease!
Is GD23 similar to a “childhood Parkinson’s Disease?” Now that this genetic link between PD and GD is here, it is time for researchers to realize that researching the babies of Gaucher’s disease with the neuronopathic type is critical to understanding Parkinson’s disease. Gaucher’s Diseases types 2 and 3 share so many of the same symptoms as Parkinson’s disease such as supranuclear gaze palsy, balance problems, fine and gross motor problems, fatigue, and swallowing problems. It cannot be just a coincidence that these two disease share so many of the same symptoms!
It is time to reach out to organizations such as the Michael J Fox foundation, the National Parkinson foundation, and the Parkinson Disease Foundation and say “Hey, our kids may hold the key to understanding your disease!”
Not only that, but the pharmaceutical companies that make Parkinson’s medications such as Sinemet, Stalevo, Parcopa, Cogentin, Artane, Eldepryl, Zelepar, and Azilect need to be looked at more closely to see if there is something within those medications that can be reformulated and used to possibly help our gaucher kids!
Association between Mutations in the Lysosomal Protein Glucocerebrosidase and Parkinsonism
A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson’s disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism. © 2009 Movement Disorder Society
Researchers believe they have found genetic cause for Parkinson’s disease
A team led by Shoji Tsuji of the University of Tokyo, and Tatsushi Toda of Kobe University discovered that those with a mutation in a gene called GBA are 28 times more likely to contract Parkinson’s disease. They now hope to use their finding to explain exactly how the disease is caused, and develop a treatment.
There are an estimated 150,000 cases of Parkinson’s disease in Japan. In 90 percent of the cases, however, they are the only members of the family to contract the condition, and the genetic component of the disease has never been identified. However, the team noticed that the GBA gene, which is responsible for causing an unusual condition called Gaucher’s disease, also showed a mutation in those with Parkinson’s disease. They examined 534 Parkinson’s patients and 544 healthy people, and found that 9.4 percent of those with the mutation suffered from the disease, and just 0.4 percent did not. They also discovered that those with the GBA mutation contracted the disease around six years earlier than those without.
“It’s the first time that a risk factor has been this clearly identified,” said Tsuji.
http://ghr.nlm.nih.gov/gene=gba
What is the official name of the GBA gene?
The official name of this gene is “glucosidase, beta; acid (includes glucosylceramidase).”
GBA is the gene’s official symbol. The GBA gene is also known by other names, listed below.
What is the normal function of the GBA gene?
The GBA gene provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Beta-glucocerebrosidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide).
How are changes in the GBA gene related to health conditions?
- Gaucher disease – caused by mutations in the GBA gene
- More than 200 mutations in the GBA gene have been identified in people with Gaucher disease. These mutations occur in both copies of the gene in each cell. Most of the GBA mutations responsible for Gaucher disease change a single protein building block (amino acid) in beta-glucocerebrosidase, altering the structure of the enzyme and preventing it from working normally. Other mutations delete or insert genetic material in the GBA gene or lead to the production of an abnormally short, nonfunctional version of the enzyme.
Mutations in the GBA gene greatly reduce or eliminate the activity of beta-glucocerebrosidase in cells. As a result, glucocerebroside is not broken down properly. This molecule and related substances can build up in white blood cells called macrophages in the spleen, liver, bone marrow, and other organs. Tissues and organs are damaged by the abnormal accumulation and storage of these substances, causing the characteristic features of Gaucher disease.
Parkinson disease – associated with the GBA gene
Growing evidence suggests an association between GBA mutations and Parkinson disease or Parkinson-like disorders that affect movement and balance (parkinsonism). People with Gaucher disease have mutations in both copies of the GBA gene in each cell, while those with a mutation in just one copy of the gene are called carriers. Some studies suggest that people with Gaucher disease and GBA mutation carriers have an increased risk of developing Parkinson disease or parkinsonism.
Symptoms of Parkinson disease and parkinsonism result from the loss of nerve cells that produce dopamine. Dopamine is a chemical messenger that transmits signals within the brain to produce smooth physical movements. It remains unclear how GBA mutations lead to these disorders. Researchers speculate that GBA mutations may contribute to the faulty breakdown of toxic substances in nerve cells by impairing the function of lysosomes, or mutations may enhance the formation of abnormal protein deposits. As a result, toxic substances or protein deposits could accumulate and kill dopamine-producing nerve cells, leading to abnormal movements and balance problems.
other disorders – associated with the GBA gene
Emerging research suggests an association between GBA mutations and a disorder called dementia with Lewy bodies. Lewy bodies are abnormal deposits of the protein alpha-synuclein that form in some dead or dying nerve cells. Specifically, they occur in nerve cells that produce a chemical messenger called dopamine. The features of this disorder are variable, but symptoms typically include a loss of intellectual functions (dementia), visual hallucinations, and fluctuations in attention. Affected individuals may also experience changes that are characteristic of Parkinson disease such as trembling or rigidity of limbs, slow movement, and impaired balance and coordination.
People with mutations in both copies of the GBA gene in each cell develop Gaucher disease, while those with a mutation in just one copy of the gene are called carriers. Research suggests that carriers have an increased risk of developing dementia with Lewy bodies, although it remains unclear how GBA mutations increase this risk. Researchers speculate that GBA mutations can alter the structure of beta-glucocerebrosidase and impair the function of lysosomes. As a result, alpha-synuclein may not be processed properly, allowing the formation of Lewy bodies.
Where is the GBA gene located?
Cytogenetic Location: 1q21
Molecular Location on chromosome 1: base pairs 153,470,866 to 153,481,111
The GBA gene is located on the long (q) arm of chromosome 1 at position 21.
More precisely, the GBA gene is located from base pair 153,470,866 to base pair 153,481,111 on chromosome 1.
See How do geneticists indicate the location of a gene? in the Handbook.
Where can I find additional information about GBA?
You and your healthcare professional may find the following resources about GBA helpful.
You may also be interested in these resources, which are designed for genetics professionals and researchers.
- PubMed – Recent literature
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OMIM – Genetic disorder catalog (2 links)
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What other names do people use for the GBA gene or gene products?
- Acid beta-glucosidase
- Alglucerase
- beta-D-glucosyl-N-acylsphingosine glucohydrolase
- Beta-glucocerebrosidase
- D-Glucosyl-N-acylsphingosine glucosylhydrolase
- GBA1
- GLCM_HUMAN
- GLUC
- Glucocerebrosidase
- Glucocerebroside beta-Glucosidase
- glucosphingosine glucosylhydrolase
- Glucosylceramidase
- Glucosylceramide beta-Glucosidase
- Imiglucerase
Where can I find general information about genes?
The Handbook provides basic information about genetics in clear language.
These links provide additional genetics resources that may be useful.
What glossary definitions help with understanding GBA?
http://www.molecularneurodegeneration.com/content/4/1/20
Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed.
In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival.
Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer’s disease, provides strong support for a role of calcium in neurodegeneration.
These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.
