Forbes Lectures

Thursday, 07/20/06 Lecture:

Genetic and Biochemical Approaches to Polyglutamine Neurodegenerative Disorders and Rett Syndrome

Huda Y. Zoghbi, Baylor College of Medicine, Howard Hughes Medical Institute
Introduction by Donald L. Price, The Johns Hopkins University School of Medicine

Lecture Abstract:

Spinocerebellar ataxia type1 (SCA1) is one of nine neurodegenerative disorders caused by expansion of CAG repeats that encode glutamine tracts in the respective proteins. We have been interested in understanding why Ataxin-1 (SCA1 gene product) becomes toxic when the number of glutamines exceeds 36. Using genetic and biochemical studies we established that the glutamine expansion endows the protein with extra activity and toxic properties. Interestingly, we found that the expanded glutamine tract modulates the activity of the AXH domain of Ataxin-1, thus establishing that some aspects of pathogenesis might involve enhanced activity of Ataxin-1. Detailed protein-protein interaction studies identified several proteins that are critical for Purkinje cell integrity and identified some molecular pathways that are likely to be involved in several cerebellar ataxias.

Friday, 07/21/06 Lecture:

Rett Syndrome and Related Disorders: Where Genetics Meets Epigenetics

Huda Y. Zoghbi, Baylor College of Medicine, Howard Hughes Medical Institute

Introduction by Bernice Grafstein, Cornell University Medical College

Lecture Abstract:

Rett syndrome (RTT) is a neurological disorder that disrupts postnatal development. RTT patients appear normal for 6-18 months and then lose the ability to speak and walk, and develop incessant hand-wringing motions as well as autistic features. RTT is caused by mutations in the transcriptional repressor, methyl CpG binding protein 2 (MeCP2). MeCP2 is believed to alter chromatin structure and histone acetylation by binding methylated cytosine residues and recruiting histone deacetylases to promoter sequences. Mutations in MECP2 cause not only Rett syndrome, but a variety of other disorders ranging from mild learning disability or autism in females to severe mental retardation, psychoses, or encephalopathy in males. MeCP2 is highly abundant in the brain, is expressed in neurons, and its appearance coincides with neuronal maturation. Mice genetically engineered to carry a truncating mutation (Mecp2308) develop most of the features of the human disease including stereotypic forelimb motions, balance problems, seizures, anxiety-like behaviors, and altered social interactions. This presentation will discuss how genetic, molecular, and electrophysiology studies are beginning to provide insight about the pathogenesis of Rett syndrome and about the role of MeCP2 in postnatal brain development and synaptic plasticity. In addition, Dr. Zoghbi will discuss how studying Rett pathogenesis could provide insight into several neuropsychiatric disorders.

Huda Y. Zoghbi is an investigator at the Howard Hughes Medical Institute, and a professor at Baylor College of Medicine. She received her B.S. in biology from The American University of Beirut in 1975 and completed her first year of medical school at the American University of Beirut in 1976. Due to the war in Lebanon, Dr. Zoghbi transferred and finished her M.D. from Meharry Medical College in 1979, and shortly after joined Baylor College of Medicine for training in pediatrics, neurology and molecular genetics. She started her first academic appointment at Baylor College in 1988 as an assistant professor in the department of pediatrics and was promoted to full professor in pediatrics, neuroscience and molecular and human genetics in 1994. Dr. Zoghbi has received numerous honors and awards including in 2004 the Marta Philipson Award for Progress in Pediatrics, Neuronal Plasticity Prize of the IPSEN Foundation and was elected to the National Academy of Sciences. She is a member of a number of committees, boards, and panels and is currently on the editorial boards of the journals Neuron, PloS, and Science.

Donald L. Price is a professor in the departments of pathology, neurology, and neuroscience, and is the director of the Alzheimer's Disease Research Center at the Johns Hopkins University School of Medicine. After receiving a B.A. from Wesleyan University and an M.D. from Albany Medical School, he trained in internal medicine in Boston and in neurology and neuropathology at Massachusetts General Hospital, completed a postdoctoral fellowship at the Biology Laboratories at Harvard University, and held the position of assistant professor at Harvard Medical School. In 1972 he moved to Hopkins. Dr. Price has made contributions to the understanding of several neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) by creating and analyzing transgenic models with phenotypes of these diseases and by using gene targeting strategies to identify and test new therapeutic targets in animals with these illnesses. He has received a variety of honors, including the MetLife Award for Research, the Potamkin Prize, and two Javits Neuroscience Investigator Awards, among others. He is a trustee of the Grass Foundation, was the President of The Society for Neuroscience, and is a member of the Institute of Medicine (National Academy of Sciences). During the "Decade of the Brain", Dr. Price was ranked by Science Watch in the top ten authors of high impact publications in neuroscience. Dr. Price has been a resident of Woods Hole for many years.

Bernice Grafstein received her B.A. from the University of Toronto and her Ph.D. from McGill University, Montreal. She did her postdoctoral work in the department of anatomy at University College London, and subsequently served on the faculty of McGill University and Rockefeller University. Since 1969 she has been a member of the department of physiology and biophysics at Cornell University Medical College where she is now professor of physiology and biophysics and the Vincent and Brooke Astor Distinguished Professor in Neuroscience. Since early in her career she has maintained an association with the Grass Foundation, first as a Grass Fellow at the MBL, and now as trustee and vice-president of the Foundation. She has been a member of the National Advisory Council for the Neurological Institute at NIH, and is now a member of the distinguished group of neuroscientists that constitute the Dana Alliance for Brain Research. Among many other services to the neuroscience community, she has served on the scientific advisory boards of a number of voluntary health organizations such as the National Spinal Cord Injury Foundation and the Research Foundation of the Paralyzed Veterans of America. She is now an active member of the Council of the Hall of Science in Flushing, New York. Dr. Grafstein has received numerous scientific awards, including, most recently, the 2003 Miriam Salpeter Women in Neuroscience Award for Lifetime Achievement. She has also received several awards for teaching from the medical students in her classes, of which she is particularly proud.

About the Forbes Lectures:
Since 1959, the special two-part Forbes Lecture has been supported by The Grass Foundation, a private foundation that supports research and education in neuroscience. The lectures are given in honor of pioneering neurobiologist Alexander Forbes. Traditionally, the Forbes lecturer also spends several weeks at the MBL, working alongside the Grass Fellowship Program.