期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 27, 页码 9947-9952出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309426111
关键词
let-7f; LIN28A
资金
- National Eye Institute Ruth L. Kirschstein Postdoctoral Fellowship [5F32EY020066-03]
- National Institutes of Health [MH085802]
- Simons Foundation
Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the beta 2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2(-/y)) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2(-/+)) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2(-/y) mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce beta 2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.
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