کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3069578 1580686 2012 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی عصب شناسی
پیش نمایش صفحه اول مقاله
Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway
چکیده انگلیسی

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.


► Genes and proteins involved in the Bdnf trafficking are deregulated in the brain of Mecp2-deficient mice.
► Mecp2-deficient mice exhibit an abnormal distribution of Bdnf throughout the cortico-striatal pathway.
► Mecp2 dosage alters in vivo the velocity of Bdnf vesicles.
► Mecp2 silencing alters App transport without affecting the mRNA and protein level.
► Cysteamine treatment improves motor function and lifespan of Mecp2-deficient mice.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 45, Issue 2, February 2012, Pages 786–795
نویسندگان
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