Drosophila model increases understanding of fragile-X syndrome
1
For personal use. Only reproduce with permission from Elsevier Ltd 701 Newsdesk Researchers are getting closer to identifying MYAS1, a locus in the human HLA complex associated with susceptibility to acquired generalised myasthenia gravis, an autoimmune neurological disorder. Henri-Jean Garchon (Institut National de la Santé et de la Recherche Médicale U580, Paris, France) and colleagues report that MYAS1 maps to the class III region of the HLA complex, a region that contains genes involved in the formation of germinal centres, struc- tures that actively produce antibodies. Myasthenia gravis is characterised by skeletal muscle weakness that increases after exercise. Respiratory muscles can also be affected, leading to respiratory failure in the most severe cases. Most patients with myasthenia gravis produce high titres of antibodies to the acetycholine receptor present at neuromuscular junctions. These antibodies impair the transmission of nerve impulses to the muscles. The commonest form of myasthenia gravis, says Garchon, “affects young women and is characterised by an anomaly of the thymus called follicular hyperplasia. The thymus of these patients effectively turns into a kind of lymph node producing autoantibodies.” By measuring the association of 27 marker genes in the HLA region with myasthenia gravis in 73 families with a single case of this common form of the disorder, Garchon and his team have localised MYAS1 to a 1·2 Mbp genome segment. They also identify a core haplotype (a set of alleles that is inherited as a block) that is strongly associated with this type of myasthenia gravis and with higher titres of antibodies against the acetylcholine receptor (Proc Natl Acad Sci USA 2004; 101: 15464–69). “Our results clearly show that class III HLA genes are involved in disease development and not class II genes [genes involved in the presentation of antigens to lymphocytes] as previously thought”, says Garchon. Possible candidate genes for MYAS1 in the region, Garchon notes, include the lymphotoxin genes, which are involved in germinal centre formation. “This is a [thought] provoking paper that suggests the possible involvement of immune response genes other than HLA I or II, in myasthenia gravis in younger patients”, comment Nick Willcox and Angela Vincent (Institute of Molecular Medicine, Oxford, UK). “The results suggest that polymorphic variants of molecules such as lymphotoxin could, for instance, influence the formation of germinal centres and lead to higher antibody titres.” Further work is now required to explain why patients develop the immune response in the first place, note both the Oxford researchers and Garchon. Jane Bradbury Homing in on myasthenia-gravis gene Neurology Vol 3 December 2004 http://neurology.thelancet.com Drosophila model increases understanding of fragile-X syndrome Fragile-X syndrome, the most common form of inherited mental retardation, is caused by a mutation in the FMR1 gene, which encodes FMRP, an RNA-binding translation regulator. What we have found is that fragile X negatively regulates neuronal structural complexity, said study author Kendal Broadie (Vanderbilt University, Nashville, TN, USA). “This misregulation exists throughout the neuron, and it leads to incorrect neural circuit contact and impaired synaptic terminal differentiation. In the patient, this means increased process formation and growth.” In a Drosophila model of fragile-X syndrome, Broadie and colleagues investigated the role of Drosophila FMRP (dFMRP) in the central brain. The researchers concentrated on the mushroom body, the insect brain’s learning and memory centre, which is thought to be analgous to the hippocampus. In mushroom-body neurons, dFMRP bidirectionally regulates several levels of structural architecture, including process formation from the soma, dendritic elaboration, axonal branching, and synaptogenesis. Analysis of the structure of Drosophila-fmr1-null mutant neurons revealed enlarged synaptic boutons, irregular bouton size, and abnormal accumulation of synaptic vesicles. These defects indicate the impairment of normal synaptogenesis, and suggest arrested synaptic function (Curr Biol 2004; 14: 1863–70). Results from a Drosophila model are applicable to the human syndrome, explained Broadie. “It is now extremely well established that Drosophila neurons are patterned and function through very highly conserved molecular and cellular pathways. Indeed, our previous work on fragile-X syndrome indicated impaired regulation of the translational control of microtubule- associated-protein 1B, leading to hyperstabilised microtubules and neuronal patterning defects. All of this work has just recently been retested and confirmed exactly in the mouse model (Proc Natl Acad Sci USA 2004; 101: 15201–06).” The results are very convincing and the quality of figures is superb, commented Rob Willemsen (Erasmus MC, Rotterdam, the Netherlands). “However, the results confirm earlier studies in Fmr1 knockout mice and Drosophila and do not show exciting new data that changes our view about cellular FMRP function.” “In addition, we have to realise that in Drosophila melanogaster only one gene is present, said Willemsen, “whereas in mammals three genes are present. Thus, to extrapolate the results obtained in Drosophila to the human situation we have to make some reservations. Some of the aspects of dFMRP that we observe in Drosophila may be due to FXR1P or FXR2P function in mammals and men.” Roxanne Nelson
-
Upload
roxanne-nelson -
Category
Documents
-
view
212 -
download
0
Transcript of Drosophila model increases understanding of fragile-X syndrome
For personal use. Only reproduce with permission from Elsevier Ltd
701
Newsdesk
Researchers are getting closer toidentifying MYAS1, a locus in thehuman HLA complex associated withsusceptibility to acquired generalisedmyasthenia gravis, an autoimmuneneurological disorder. Henri-JeanGarchon (Institut National de la Santéet de la Recherche Médicale U580,Paris, France) and colleagues reportthat MYAS1 maps to the class IIIregion of the HLA complex, a regionthat contains genes involved in theformation of germinal centres, struc-tures that actively produce antibodies.
Myasthenia gravis is characterisedby skeletal muscle weakness thatincreases after exercise. Respiratorymuscles can also be affected, leading torespiratory failure in the most severecases. Most patients with myastheniagravis produce high titres of antibodiesto the acetycholine receptor present atneuromuscular junctions. Theseantibodies impair the transmission ofnerve impulses to the muscles.
The commonest form ofmyasthenia gravis, says Garchon,“affects young women and ischaracterised by an anomaly of thethymus called follicular hyperplasia.The thymus of these patientseffectively turns into a kind of lymphnode producing autoantibodies.”
By measuring the association of 27marker genes in the HLA region withmyasthenia gravis in 73 families with asingle case of this common form of thedisorder, Garchon and his team havelocalised MYAS1 to a 1·2 Mbp genomesegment. They also identify a corehaplotype (a set of alleles that isinherited as a block) that is stronglyassociated with this type of myastheniagravis and with higher titres ofantibodies against the acetylcholinereceptor (Proc Natl Acad Sci USA2004; 101: 15464–69).
“Our results clearly show that classIII HLA genes are involved in diseasedevelopment and not class II genes
[genes involved in the presentation ofantigens to lymphocytes] as previouslythought”, says Garchon. Possiblecandidate genes for MYAS1 in theregion, Garchon notes, include the lymphotoxin genes, which areinvolved in germinal centre formation.
“This is a [thought] provokingpaper that suggests the possibleinvolvement of immune responsegenes other than HLA I or II, inmyasthenia gravis in youngerpatients”, comment Nick Willcox andAngela Vincent (Institute of MolecularMedicine, Oxford, UK). “The resultssuggest that polymorphic variants ofmolecules such as lymphotoxin could,for instance, influence the formationof germinal centres and lead to higherantibody titres.” Further work is nowrequired to explain why patientsdevelop the immune response in thefirst place, note both the Oxfordresearchers and Garchon.Jane Bradbury
Homing in on myasthenia-gravis gene
Neurology Vol 3 December 2004 http://neurology.thelancet.com
Drosophila model increases understanding of fragile-X syndrome
Fragile-X syndrome, the mostcommon form of inherited mentalretardation, is caused by a mutationin the FMR1 gene, which encodesFMRP, an RNA-binding translationregulator. What we have found isthat fragile X negatively regulatesneuronal structural complexity, saidstudy author Kendal Broadie(Vanderbilt University, Nashville,TN, USA). “This misregulation existsthroughout the neuron, and it leadsto incorrect neural circuit contactand impaired synaptic terminaldifferentiation. In the patient, thismeans increased process formationand growth.”
In a Drosophila model of fragile-Xsyndrome, Broadie and colleaguesinvestigated the role of DrosophilaFMRP (dFMRP) in the central brain.The researchers concentrated on themushroom body, the insect brain’slearning and memory centre, which isthought to be analgous to thehippocampus. In mushroom-bodyneurons, dFMRP bidirectionally
regulates several levels of structuralarchitecture, including processformation from the soma, dendriticelaboration, axonal branching, andsynaptogenesis. Analysis of thestructure of Drosophila-fmr1-nullmutant neurons revealed enlargedsynaptic boutons, irregular boutonsize, and abnormal accumulation ofsynaptic vesicles. These defectsindicate the impairment of normalsynaptogenesis, and suggest arrestedsynaptic function (Curr Biol 2004; 14:1863–70).
Results from a Drosophila modelare applicable to the humansyndrome, explained Broadie. “It isnow extremely well established thatDrosophila neurons are patterned andfunction through very highlyconserved molecular and cellularpathways. Indeed, our previous workon fragile-X syndrome indicatedimpaired regulation of thetranslational control of microtubule-associated-protein 1B, leading tohyperstabilised microtubules and
neuronal patterning defects. All of thiswork has just recently been retestedand confirmed exactly in the mousemodel (Proc Natl Acad Sci USA 2004;101: 15201–06).”
The results are very convincingand the quality of figures is superb,commented Rob Willemsen (ErasmusMC, Rotterdam, the Netherlands).“However, the results confirm earlierstudies in Fmr1 knockout mice andDrosophila and do not show excitingnew data that changes our view aboutcellular FMRP function.”
“In addition, we have to realisethat in Drosophila melanogaster onlyone gene is present, said Willemsen,“whereas in mammals three genes arepresent. Thus, to extrapolate theresults obtained in Drosophila to thehuman situation we have to makesome reservations. Some of theaspects of dFMRP that we observe inDrosophila may be due to FXR1P orFXR2P function in mammals andmen.”Roxanne Nelson
