Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness

8 Aug by Mommy

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]

~ Filed Under: Gaucher's Disease

Parkinsonism in Gaucher’s disease type 1: Ten new cases and a review of the literature

30 Jun by Mommy

http://www3.interscience.wiley.com/journal/122441884/abstract?CRETRY=1&SRETRY=0

Frédéric Sedel (frederic.sedel@psl.aphp.fr)

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
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
~ Filed Under: Gaucher's Disease

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

30 Jun by Mommy

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 {alpha}-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

~ Filed Under: Gaucher's Disease

Impaired IL-10 transcription and release in animal models of Gaucher disease macrophages

30 Jun by Mommy

http://www.ncbi.nlm.nih.gov/pubmed/19380242?dopt=Abstract

Kacher Y, Futerman AH.

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.

~ Filed Under: Gaucher's Disease

Mutations for Gaucher disease linked to high risk of Parkinson’s disease

20 Jun by Mommy

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.

 
However, numerous studies have linked pathogenic mutations within GBA with increased susceptibility to Parkinson’s disease. In perhaps the most definitive work to date [Mitsui J et al. (2009) Arch Neurol 66(5):571-6], researchers resequenced the GBA gene in over 500 cases of Parkinson’s disease and matched controls; whilst only 2 of the control subjects had any of the pathogenic mutations associated with Gaucher disease, 50 of the cases were heterozygous for one of 11 mutations in the gene. Having one of these mutations therefore confers a substantial and significant increased risk of developing Parkinson’s disease of nearly 30-fold (OR = 28.0, 95% confidence intervals 7.3-238.3), though individual mutations may be associated with various lower risks [Gan-Or Z et al. (2008) Neurology 70(24):2277-83]. In addition, patients with mutations in GBA were significantly younger at the age of onset of Parkinson’s disease than those without. In contrast, there was no statistically significant association between non-pathogenic mutations in GBA and Parkinson’s disease.
 
Comment: This research is important for three different reasons. First, by combining numerous pathogenic mutations in the GBA gene in a relatively large study, the work unifies various earlier and smaller studies linking the gene with Parkinson’s disease.
 
Second, it highlights a general paradigm shift from the common disease-common variant hypothesis within human genetics, which underlies the recent plethora of genome-wide association (GWA) studies, to the common disease-rare variant hypothesis. If the majority of genetic risk for common diseases is actually located in rare variants, not common polymorphisms, conducting resequencing analysis of specific susceptibility genes is the logical next step in the hunt for the genetic basis for all common diseases. Adopting such a strategy could therefore be substantially more fruitful than conducting ever larger GWA studies.
 
Third, and perhaps most significantly, the work raises serious ethical concerns over carrier screening for Gaucher disease, particularly within the Ashkenazi Jewish population (see previous news). According to the National Gaucher Foundation, the carrier status may be as high as 1 in 15 amongst Jewish people of Eastern European ancestry (and 1 in 100 amongst the general population). The current policy of the UK National Screening Committee is that carrier testing for Gaucher disease should not be offered, as it is treatable and can be relatively mild. However, those who are considering getting tested privately prior to becoming pregnant may now want to think again; a relative risk of ~30 is one of the largest genetic risks known, and may even have predictive ability (though further research is needed here). As Parkinson’s disease has a UK population prevalence of around 1% in the over 65’s (based on data from the Parkinson’s Disease Society), such information could potentially have enormous personal and societal consequences. Additionally, authorities face an even greater challenge – should people who have already had carrier testing be informed of the associated risk of Parkinson’s disease, or not?
 
Such ethical conundrums are only likely to increase as more and more genetic susceptibilities are discovered that have relevance to multiple diseases. To date, this has been a relatively small problem, as most of the susceptibilities discovered through GWA studies have been associated with extremely low risks (OR<2) and have very limited predictive ability. However, if the common disease-rare variant hypothesis is correct, we can expect significantly more issues of this nature to surface over the coming years. Policymakers and clinicians will need to bear this in mind when forming national guidance regarding genetic testing and screening.
~ Filed Under: Gaucher's Disease
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