Role of the adipocyte hormone leptin in the pathogenesis of Rett syndrome
Yasmine Belaidouni
Team “Perinatal Imprintings and Neurodevelopmental Disorders”
Abstract
Rett syndrome is a neurodevelopmental disorder that affects mainly girls and represents the second cause of intellectual disability of genetic origin in women. After an apparent normal development until approximately 18 months, RTT is characterized by loss of language, loss of walking, hand stereotypies, breathing difficulties and epileptic seizures. RTT is caused by mutations of the X-linked Methyl-CpG-binding protein 2 (MECP2) gene, encoding for a transcriptional regulator, essential for the development and maintenance of synapses. Currently, there is no cure for this disease. Among the various biological and neurochemical alterations observed in this syndrome, clinical and experimental studies have reported abnormal elevated levels of leptin in patients and animal models.
Leptin is a hormone released mainly from adipocytes and represents a key factor in maintaining energy balance. In addition to this canonical function, leptin regulates several other functions such as anxiety, breathing or cognitive processes, which are altered in the case of this syndrome. Therefore, abnormal elevated leptin levels could contribute to the alterations observed in RTT. The objective of my thesis was to determine the role played by leptin in this pathology by targeting the leptinergic system in a mouse model of the pathology (mice deficient in Mecp2: Mecp2-/y). Treatment aimed at blocking leptin transport across the blood-brain barrier during the symptomatic period restored the excitation/inhibition balance in the hippocampus, prevented weight loss and slowed the progression of respiratory symptoms of Mecp2-/y mice. Conversely, leptin of wild-type mice altered the excitation/inhibition balance in the hippocampus, led to weight loss and increased the number of apneas phenotyping the Mecp2-/y mice.
This work has revealed a new role for leptin in the pathogenesis of Rett syndrome, thus offering new therapeutic perspectives.
Jury
Thierry Bienvenu, Examinateur – UMR 1266, IPNP, Paris
Jean-Christophe Roux, Examinateur – UMR S1251, MMG, Marseille
Laurence Bodineau, Rapportrice – UMR S1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Paris
Sébastien Bouret , Rapporteur – UMR S1172, Lille Neuroscience et cognition, Lille
Laurent Aniksztejn, Président – UMR 1249, Inmed, Marseille
Jean-Luc Gaiarsa, Directeur de thèse – UMR 1249, Inmed, Marseille
Wednesday June 22nd at 2pm – Inmed conference room