title: Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway.
abstract: Mecp2 deficiency or overexpression causes a wide spectrum of neurological diseases in humans among which Rett Syndrome is the prototype. Pathogenic mechanisms are thought to involve transcriptional deregulation of target genes such as Bdnf together with defects in the general transcriptional program of affected cells. Here we found that two master genes, Huntingtin (Htt) and huntingtin-associated protein (Hap1), involved in the control of Bdnf axonal transport, are altered in the brain of Mecp2-deficient mice. We also revealed an in vivo defect of Bdnf transport throughout the cortico striatal pathway of Mecp2-deficient animals. We found that the velocity of Bdnf-containing vesicles is reduced in vitro in the Mecp2-deficient axons and this deficit can be rescued by the re-expression of Mecp2. The defect in axonal transport is not restricted to Bdnf since transport of the amyloid precursor protein (App) that is Htt and Hap1-dependent is also altered. Finally, treating Mecp2-deficient mice with cysteamine, a molecule increasing the secretion of Bdnf vesicles, improved the lifespan and reduced motor defects, suggesting a new therapeutic strategy for Rett syndrome.
authors: INSERM, UMR_S 910, Faculté de Médecine de La Timone, Marseille, F-13385, France. jean-christophe.roux@univmed.fr
authors: Jean-Christophe
authors: JC
authors: Roux
authors: Diana
authors: D
authors: Zala
authors: Nicolas
authors: N
authors: Panayotis
authors: Ana
authors: A
authors: Borges-Correia
authors: Frédéric
authors: F
authors: Saudou
authors: Laurent
authors: L
authors: Villard
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D000071058:Huntingtin Protein; D007150:Immunohistochemistry; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C490758:Hap1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins