Huda Zoghbi (BCM/TCH) 2: Pathogenesis of MeCP2 Disorders скачать в хорошем качестве

Huda Zoghbi (BCM/TCH) 2: Pathogenesis of MeCP2 Disorders

https://www.ibiology.org/human-diseas... Dr. Huda Zoghbi’s seminar takes us through the scientific journey from discovering the cause of Rett Syndrome to testing possible treatments for MECP2 disorders. Dr. Huda Zoghbi's work has provided insight into Autism Spectrum Disorders (ASD) by focusing on Rett Syndrome, a postnatal progressive neurological disorder. By studying the genetics of Rett Syndrome, her group made the seminal discovery of X-linked Methyl CpG-binding protein 2 (MECP2) as the gene that causes Rett Syndrome. Zoghbi’s group showed that the severity of the disease was highly dependent on the amount of functional MeCP2 protein expressed. Females, who carry one normal and mutant MECP2 allele typically suffer from Rett syndrome, but the amount of functional protein is influenced by X-chromosome inactivation, and girls with more cells expressing normal allele have milder features. Surprisingly, they also showed that duplications spanning MECP2 can cause a Rett-like progressive neurological disease, highlighting the importance of MeCP2 levels for neural functions. Zoghbi describes how these findings have spurred new research into how MeCP2 affects postnatal development and brain function. In her second lecture, Zoghbi explains how MeCP2 molecularly modulates neuronal function. Their studies uncovered a critical link between cytosine methylation, MeCP2, and the methylating enzyme Dnmt3a, in Rett Syndrome. They hypothesized that MeCP2 partially causes Rett-Syndrome symptoms by failure of reading methylated DNA marked by Dnmt3 and indeed showed that Dnmt3-dependent mCH plays a central role in Rett pathogenesis. In her third lecture, Zoghbi explores possible therapies for MECP2 disorders. First, using Deep Brain Stimulation (DBS), Zoghbi’s team together with collaborator Dr. Jianrong Tang were able to rescue learning and memory deficits, enhance neurogenesis, correct abnormal neural network activity, and improve MeCP2-linked gene expression changes in a mouse model of Rett Syndrome. Then, she discusses two approaches to normalize the MeCP2 protein in MECP2 duplication mice: by deleting the duplicated MECP2 gene in the genome, or by decreasing MECP2 mRNA levels using antisense-oligonucleotides. Even though these two approaches seem to rescue developmental issues caused by MECP2 duplication, titrating MeCP2 levels is required in order to avoid Rett-like symptoms caused by lowering the protein too much. Speaker Biography: Dr. Huda Zoghbi is the Ralph D. Feigin professor at Baylor College of Medicine, an investigator at the Howard Hughes Medical Institute, and the director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. She started her studies in biological sciences and did one year of medical school at the American University of Beirut in Lebanon. But due to the Lebanese Civil War, after her first year of medical school she moved to the United States and completed her medical degree in 1979 at Meharry Medical College. She did her pediatric residency at Baylor College of Medicine and Texas Children's Hospital. She continued her training as a fellow in pediatric neurology at the Baylor College of Medicine. Realizing the plight of children with devastating neurological diseases of unknown causes she pursued postdoctoral training in molecular biology and genetics with Dr. Arthur L. Beaudet in 1985. Since 1988, Zoghbi has been a faculty member at Baylor College of Medicine where her lab uses genetic, biomedical, and cell biological approaches to study brain development and degeneration. She is particularly interested in understanding neurodegenerative diseases and Rett syndrome. Zoghbi has worked with Rett Syndrome patients since 1983, and it was her curiosity about the genetics of this disease that led to the discovery of MECP2 as the gene responsible for this sporadic neurological disease. For her scientific contributions, Zoghbi was awarded the Breakthrough Prize in Life Sciences (2017), the Canada Gairdner International Award (2017), and the Shaw Prize in Life Science and Medicine (2016). In addition, she is an elected member of the American Academy of Arts and Sciences (2018), the National Academy of Sciences (2004), and the National Academy of Medicine (2000). Visit her lab website, and learn more about Zoghbi’s research: https://www.bcm.edu/research/labs/hud...