Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism
August 10, 2009 by Mommy
Filed under Gaucher's - Research, Parkinson's Link
http://www.ncbi.nlm.nih.gov/pubmed/19576930?dopt=Abstract
The Parkinson’s Institute, 675 Almanor Ave., Sunnyvale, CA 94085, USA.
A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson’s disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.
PMID: 19576930 [PubMed - as supplied by publisher]
Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness
August 8, 2009 by Mommy
Filed under Gaucher's - Research
http://www.ncbi.nlm.nih.gov/pubmed/19651460?dopt=Abstract
IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal.
Gaucher disease (GD) is associated with upregulation of CD1d and MHC-class II expression by monocytes. While the physiological impact of CD1d upregulation remains uncertain, it has been proposed that MHC-class II upregulation is associated with inflammation. Hereby, we show that the decrease in MHC-class II expression seen in GD patients under therapy correlates positively with chitotriosidase activity, a marker of inflamed macrophages. We also show that retinoic acid (RA) and the beta-glucocerebrosidase inhibitor conduritol-B-epoxide (CBE) lead to upregulation of CD1d expression by THP-1 cells, which correlated with an increase in mRNA expression. In vitro co-culture experiments showed that RA treated THP-1 cells were more stimulatory for CD4(+) than for CD8(+) T cells, as determined by CFSE loss, in comparison to untreated THP-1 cells. Interestingly, even though addition of exogenous isoglobotrihexosylceramide (iGb3), a physiological CD1d ligand, augmented the percentage of dividing CD4(+) T cells, we could not detect a significant expansion of CD4(+)Valpha24(+) invariant Natural Killer T (iNKT) cells. In contrast, addition of alpha-galactosylceramide (alpha-GC) induced expansion of Valpha24(+) iNKT cells as determined by using alpha-GC-loaded human CD1d dimers. These results strengthen the existence of a cross-talk between monocyte lipid accumulation, inflammation and changes in cell surface CD1d and MHC-class II in monocytes, which may result in inappropriate recognition events by immune cells and perpetuate chronic inflammation.
PMID: 19651460 [PubMed - as supplied by publisher]
Parkinsonism in Gaucher’s disease type 1: Ten new cases and a review of the literature
June 30, 2009 by Mommy
Filed under Gaucher's - Research
http://www3.interscience.wiley.com/journal/122441884/abstract?CRETRY=1&SRETRY=0
| Ichraf Kraoua, MD 1, Jérôme Stirnemann, MD 2, Maria João Ribeiro, MD, PhD 3, Tiphaine Rouaud, MD 4, Marc Verin, MD, PhD 4, Agnès Annic, MD 5, Christian Rose, MD, PhD 6, Luc Defebvre, MD, PhD 5, Liliane Réménieras, MD 7, Michaël Schüpbach, MD 1, Nadia Belmatoug, MD 8, Marie Vidailhet, MD 1 9, Frédéric Sedel, MD, PhD 1 * | ||
| 1Federation of Nervous System Diseases, Reference Center for Lysosomal Diseases, Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, France 2Department of Internal Medicine, Jean Verdier Hospital, Assistance Publique-Hôpitaux de Paris, Paris X111 University, France 3Service Hospitalier Frédéric Joliot, I2BM, DSV, CEA, Orsay, France 4Department of Neurology, University Hospital of Rennes, Rennes, France 5Department of Neurology, University Hospital of Lille, Lille, France 6Department of Onco-Haematology, Saint Vincent de Paul Hospital, Lille, France 7Department of Haematology, University Hospitals of Limoges, Limoges, France 8Department of Internal Medicine, Reference Center for Lysosomal Diseases, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, France 9INSERM U679, Pierre et Marie Curie (Paris 6) University, France |
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| email: |
*Correspondence to Frédéric Sedel, Federation of Nervous System Diseases and Reference Centre for Lysosomal Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651 Paris cedex 13, France
Potential conflict of interest: None reported.
Funded by:
Genzyme
| Keywords |
| Gaucher • glucocerebrosidase • parkinsonism • Parkinson’s disease • Lewy body dementia |
| Abstract |
| Parkinsonism has been described in patients with Gaucher’s disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting. © 2009 Movement Disorder Society |
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease
June 30, 2009 by Mommy
Filed under Gaucher's - Research
http://brain.oxfordjournals.org/cgi/content/short/132/7/1783?rss=1
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease
Juliane Neumann1,2, Jose Bras3,4,*, Emma Deas1,*, Sean S. O’Sullivan1, Laura Parkkinen1, Robin H. Lachmann1, Abi Li1, Janice Holton1, Rita Guerreiro3,4, Reema Paudel1, Badmavady Segarane1, Andrew Singleton3, Andrew Lees1, John Hardy1, Henry Houlden1, Tamas Revesz1 and Nicholas W. Wood1
1 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, and Reta Lila Weston Institute, Institute of Neurology, London, UK 2 International Graduate Program Medical Neurosciences, Charité University Hospital, Berlin, Germany 3 Molecular Genetics Unit, Laboratory of Neurogeneticso, National Institutes on Aging, National Institutes of Health, Bethesda, Maryland, USA 4 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Correspondence to: Nicholas W. Wood, Institute of Neurology, Queen Square House, Queen Square, WC1N 3BG London, UK E-mail: n.wood@ion.ucl.ac.uk
Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher’s disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher’s disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson’s disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson’s disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson’s disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant 
-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith’s limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson’s disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson’s disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson’s disease and suggest that to date, this is the most common genetic factor identified for the disease.
Key Words: Parkinson’s disease; GBA; Gaucher’s disease; neuropathology
Abbreviations: AC, amygdaloid complex; BFB, basal forebrain; DMV, dorsal motor nucleus of vagus; GBA, glucocerebrosidase; HRC, human random control; LC, locus ceruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra
Impaired IL-10 transcription and release in animal models of Gaucher disease macrophages
June 30, 2009 by Mommy
Filed under Gaucher's - Research
http://www.ncbi.nlm.nih.gov/pubmed/19380242?dopt=Abstract
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
A number of studies have shown altered cytokine levels in serum from Gaucher disease patients, including changes in levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the source of IL-10, or the mechanisms leading to changes in IL-10 serum levels are not known. We now show that mouse macrophages treated with an active site-directed inhibitor of glucocerebrosidase, or macrophages from a mouse model of Gaucher disease, the L444P mouse, release significantly less IL-10 than their untreated counterparts, but that TNFalpha release is unaffected. These changes are due to reduced transcription of IL-10 mRNA in macrophages. The reduction in IL-10 secretion observed in animal models of Gaucher disease macrophages may be of relevance to explain the increase in inflammation that is often observed in Gaucher disease.
Publication Types:
PMID: 19380242 [PubMed - in process] Kacher Y, Futerman AH.
Mutations for Gaucher disease linked to high risk of Parkinson’s disease
June 20, 2009 by Mommy
Filed under Parkinson's Link
http://www.phgfoundation.org/news/4676/
What’s the connection between Gaucher disease, a rare single gene disorder of metabolism that appears during childhood, and Parkinson’s disease, a common multifactorial disorder of the nervous system that occurs late in life? The answer lies in just a single gene (glucocerebrosidase or GBA), which encodes an enzyme required for lipid metabolism and storage within the lysosome. Numerous pathogenic mutations in this gene have been characterised, which result in Gaucher disease if present in both copies of the gene; these recessive mutations are generally assumed to be relatively harmless to the carrier.
Sly Syndrome: Delivering Medicine To Fight Rare Genetic Disorder
May 25, 2009 by Mommy
Filed under Gaucher's - Research
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.
