Dartmouth Life Sciences Symposium History: 2005
2005: Mechanisms of Brain Disorders
Co-hosted by:
Joyce DeLeo, Ph.D., Director of the Neuroscience Center at Dartmouth, Professor of Anesthesiology and Pharmacology/Toxicology and Surachai Supattapone, M.D., Ph.D., D.Phil., Assistant Professor of Biochemistry and of Medicine (Infectious Disease)
Speakers
Allan I. Basbaum, Ph.D.
Professor and Chair, Department of Anatomy
W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco
http://www.ucsf.edu/neurosc/faculty/neuro_basbaum.html
Allan Basbaum did his undergraduate work with Ronald Melzack at McGill University in Montreal and received his PhD from the University of Pennsylvania. He did postdoctoral research with Patrick Wall at University College London. He is presently Professor and Chair of the Department of Anatomy at the University of California San Francisco and is a member of the W.M. Keck Foundation Center for Integrative Neuroscience. His research interests concern the transmission and control of "pain" messages and the molecular mechanisms that contribute to tissue and nerve-injury induced persistent pain. He has served on the Council and as the Treasurer of the International Association for the Study of Pain and is presently Editor-in-Chief of Pain. He received the F.W.L. Kerr Memorial Award from the American Pain Society, the Bristol Myers Squibb Prize for Distinguished Pain Research and is a Fellow of the American Academy of Arts and Sciences.
Pain Mechanisms: From Molecules to Circuits
Abstract
The molecular biology revolution has significantly impacted pain research. Perhaps the greatest influence has been on the molecular characterization of the primary afferent nociceptor, which expresses a host of molecules that are not found or are only minimally expressed elsewhere in the CNS. Among these molecules are subtypes of sodium channels, G protein-lined receptors, purinergic receptors and even water channels. Studies in mice with gene deletions established that at least some of these molecules are critical contributors to the processing of "pain" messages. A key question is the extent to which these molecules are also potential therapeutic targets for pain therapy. A related question concerns the central circuits engaged by nociceptors that express these different molecules. Specifically, although the traditional "pain" pathway is rather straightforward in the way textbooks depict it, there is now considerable evidence for a remarkable heterogeneity of the circuits engaged by different subtypes of primary afferent nociceptor. More importantly, perhaps, these circuits are modified in the setting of tissue or nerve injury. In this presentation I will highlight examples of specific molecular targets that have been identified from analyses of the primary afferent nociceptor (notably the capsaicin receptor, TRPV1). I will also address the complexity of the primary afferent synapse via an analysis of the mechanism of action of triptans in the treatment of migraine. Finally, I will introduce a new approach to evaluating "pain" pathways, using mice in which transneuronal tracers can be induced in subpopulations of primary afferent nociceptors, so as to identify the central circuits with which they interact.
Mel B. Feany, M.D., Ph.D.
Assistant Professor of Pathology
Department of Pathology, Harvard Medical School and Brigham and Women's Hospital
http://feany-lab.bwh.harvard.edu/
Parkinson's Disease: "Studying human neurodegenerative diseases in Drosophila"
Abstract
A number of human neurodegenerative diseases have now been modeled in the fruit fly Drosophila, including Parkinson's disease, Alzheimer's disease and Huntington's disease. In our laboratory we have focused on flies expressing human alpha-synuclein as a model for Parkinson's disease and tau transgenic Drosophila as a model related to Alzheimer's disease and other tauopathies. By performing forward genetic screens and candidate testing in these models we have identified a number of pathways controlling neurotoxicity in our Parkinson and tauopathy models. Phosphorylation has emerged from these studies as a key regulator of toxicity in both alpha-synuclein and tau transgenic flies.
Alan I. Green, M.D.
Raymond Sobel Professor of Psychiatry and Chair
Department of Psychiatry, Dartmouth Medical School/Dartmouth-Hitchcock Medical Center
Mental Illness: "Schizophrenia and Substance Abuse: A Reward Deficiency Syndrome?"
DMS Faculty Profile
Jeffrey D. Rothstein M.D., Ph.D.
Professor of Neurology and Neuroscience
Department of Neurology, Johns Hopkins University
ALS (Lou Gehrig's Disease): "Transporter regulation as a target for neurotherapeutics: Rediscovery of penicillin"
http://www.alscenter.org/scientists/scientists_rothstein.htm
Dennis J. Selkoe, M.D.
Vincent and Stella Coates Professor of Neurologic Diseases
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital
Alzheimer's Disease: "Presenilin, APP, and the Origins of Alzheimer's Disease" http://selkoelab.bwh.harvard.edu/
Dennis J. Selkoe, MD, the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School and Brigham and Women's Hospital, has devoted his career to the study of Alzheimer's disease (AD), Parkinson’s disease and related basic biological questions. A graduate of Columbia University and the University of Virginia School of Medicine, he trained at the National Institutes of Health, the Harvard/Longwood Neurology Program and in the Department of Neuroscience, HMS. Selkoe originally developed a method for isolating the neurofibrillary tangles that are a hallmark of AD and discovered their unusual properties. Subsequently, he conducted extensive experiments on amyloid ß-protein (Aß) and its precursor and helped formulate a theory of AD causation (the “amyloid hypothesis”). Selkoe and colleagues discovered that Aß is produced by normal cells throughout life, leading to the use of cultured cells to study how Aß is formed and to identify Aß inhibitors. The lab showed that mutations in APP and presenilin cause AD by increasing Aß production. Selkoe and collaborators conducted the experiments identifying presenilin as the active site of γ-secretase, an unprecedented intramembrane aspartyl protese that cleaves APP, Notch and other proteins. These and other advances have led to his receipt of the Potamkin Prize (shared with George Glenner), the A.H. Heineken Price for Medicine,and the Metropolitan Life Award for Medial Research, among others. Selkoe was the principal founding scientist of Athena Neurosciences, now Elan, plc. He has served on numerous editorial boards, the Neuroscience Review Committee of HHMI, and the National Advisory Council on Aging.
Surachai Supattapone, M.D., Ph.D., D.Phil.
Associate Professor of Biochemistry and of Medicine
Department of Biochemistry, Dartmouth Medical School
http://dms.dartmouth.edu/supattapone/
Dr. Supattapone was born 1965 in Bangkok, Thailand. His education includes Chemistry Honors Johns Hopkins University in Baltimore, Maryland (1984); D.Phil. Physiology Oxford University, England as a Rhodes Scholar (1991); M.D. and Ph.D. Neuroscience Johns Hopkins University School of Medicine (1992), where his thesis project identified the inositol trisphosphate (IP3) receptor under the mentorship of Solomon H. Snyder. From 1992-1994, Dr. Supattapone was a resident in Internal Medicine at Massachusetts General Hospital, Boston, Massachusetts. In 1994-1995, he was a Fellow in Infectious Diseases at UCSF in San Francisco, California, after which he became a Post-doctoral fellow, Adjunct Instructor, and Adjunct Assistant Professor at UCSF working under the mentorship of Stanley B. Prusiner on research projects such as structure-function analysis of the prion protein, discovery of branched polyamine dendrimers as potential prion therapeutics, and invention of a non-corrosive prion disinfectant. In 1998, Dr. Supattapone received both the Burroughs Wellcome Career Development Award and the National Institutes of Health (NIH) physician-scientist (K08) award. He joined the faculty of Dartmouth Medical School in 2001, where he is currently an Associate Professor of Biochemistry and Medicine, and where he and his colleagues are studying the pathogenesis of prion disease.
Prion Disease: "Biochemical Studies of Prion Disease Pathogenesis"
Abstract
Prions, the infectious agents of transmissible spongiform encephalopathies, are composed primarily of a misfolded protein designated PrPSc. Prion-infected neurons generate PrPSc from a host glycoprotein designated PrPC through a process of induced conformational change, but the molecular mechanism by which PrPC undergoes conformational change into PrPSc remains unknown. We are employing an in vitro amplification technique adapted from the Protein Misfolding Cyclic Amplification (PMCA) method of Saborio and Soto to investigate the mechanism of prion-induced protein conformational change biochemically. Using this system, host requirements for PrPres amplification can be studied biochemically. The results of ongoing investigations using this approach will be discussed.