eBriefing

Neurodegenerative Diseases

Neurodegenerative Diseases
Reported by
Adrian Ivinson

Posted September 24, 2009

Overview

Although much progress toward understanding neurodegenerative diseases has been made in recent years, few effective treatments and no cures are currently available. There is however reason for optimism. We know more than ever about how these diseases develop and progress, and the research community is exploring many new and exciting ideas that will lead to better diagnosis, new treatments and, ultimately, cures.

Each year the Harvard Center for Neurodegeneration & Repair organizes a major symposium on biomedical research relating to the understanding and treatment of neurodegenerative diseases. The translational theme provides speakers with an opportunity to present recent results and to discuss their relevance to therapy. This year's conference featured presentations by 9 leaders in the field.

With a dominant focus on Alzheimer's disease, Parkinson's disease, and ALS, this symposium was purposely designed to jump around a variety of themes including basic mechanistic understanding of disease, drug discovery, and clinical trials.

This special eBriefing contains audio and slides presented at the conference, along with background information about the speakers and links to additional resources.

Use the tabs above to find multimedia and additional information.


Speakers in this eBriefing:

Karen Hsiao Ashe (Unversity of Minnesota Medical School)
Robert H. Brown, Jr. (Massachusetts General Hospital)
Ted Dawson (Johns Hopkins University School of Medicine)
Michael S. Wolfe (Brigham & Women's Hospital, Harvard Medical School)
Paul Greengard (The Rockefeller University)
Connie Cepko (Harvard Medical School)
Reisa A. Sperling (Brigham & Women's Hospital)
Peter T. Lansbury, Jr. (Brigham & Women's Hospital)
Dale Schenk (Elan Corporation)


Presented by

The Harvard Center for Neurodegeneration & Repair

Journal Articles

Karen Ashe

Ashe, K. H. 2005. Mechanisms of memory loss in Abeta and tau mouse models. Biochem. Soc. Trans. 33: 591-594.

Cleary, J. P., D. M. Walsh, J. J. Hofmeister, et al. 2005. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 8: 79-84.

Lesne, S., M. T. Koh, L. Kotilinek, et al. 2006. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440: 352-357.

Ramsden, M., L. Kotilinek, C. Forster, et al. 2005. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J. Neurosci. 25: 10637-10647.

Santacruz, K., J. Lewis, T. Spires, et al. 2005. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309: 476-481.

Robert Brown

Boston-Howes, W., S. L. Gibb, E. O. Williams, et al. 2006. Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J. Biol. Chem. 281: 14076-14084.

Broom, W. J., I. Ay, P. Pasinelli, et al. 2006. Inhibition of SOD1 expression by mitomycin C is a non-specific consequence of cellular toxicity. Neurosci. Lett. 393: 184-188.

Hadano, S., S. C. Benn, S. Kakuta, et al. 2006. Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum. Mol. Genet. 15: 233-250.

Morita, M., A. Al-Chalabi, P. M. Andersen, et al. 2006. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66: 839-844.

Pasinetti, G. M., L. H. Ungar, D. J. Lange, et al. 2006. Identification of potential CSF biomarkers in ALS. Neurology 66: 1218-1222.

Ted Dawson

Chung, K. K., B. Thomas, X. Li, et al. 2004. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304: 1328-1331.

Dawson, T. M. 2005. Failures and successes of clinical trials for Parkinson disease treatments. Retina 25: S75-S77.

Hong, S. J., V. L. Dawson, & T. M. Dawson. 2005. Identification and evaluation of NO-regulated genes by differential analysis of primary cDNA library expression (DAzLE). Methods Enzymol. 396: 359-368.

Ko, H. S., R. von Coelln, S. R. Sriram, et al. 2005. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J. Neurosci. 25: 7968-7978. Full Text

Savitt, J. M., V. L. Dawson & T. M. Dawson. 2006. Diagnosis and treatment of Parkinson disease: molecules to medicine. J. Clin. Invest. 116: 1744-1754. Full Text

Smith, W. W., Z. Pei, H. Jiang, et al. 2005. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. 102: 18676-18681. Full Text

von Coelln, R., B. Thomas, S. A. Andrabi, et al. 2006. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J. Neurosci. 26: 3685-3696.

West, A. B., D. J. Moore, S. Biskup, et al. 2005. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102: 16842-16847. Full Text

Michael Wolfe

Bakshi, P., Y. F. Liao, J. Gao, et al. 2005. A high-throughput screen to identify inhibitors of amyloid beta-protein precursor processing. J. Biomol. Screen. 10: 1-12.

Cowan, J. W., X. Wang, R. Guan, et al. 2005. Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. J. Biol. Chem. 280: 19331-19342.

Fraering, P. C., W. Ye, M. J. LaVoie, et al. 2005. Gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J. Biol. Chem. 280: 41987-41996.

Kornilova, A. Y., F. Bihel, C. Das, et al. 2005. The initial substrate-binding site of γ-secretase is located on presenilin near the active site. Proc. Natl. Acad. 102: 3230-3235. Full Text

Urban, S. & M. S. Wolfe. 2005. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc. Natl. Acad. 102: 1883-1888. Full Text

Paul Greengard

Cai, D. M., M. H. Zhong, & R. S. Wang. 2006. Phospholipase D1 corrects impaired beta APP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc. Nat. Acad. Sci. 103: 1936-1940.

Chergui, K , P. Svenningsson, & P. Greengard. 2005. Physiological role for casein kinase 1 in glutamatergic synaptic transmission. J. Neurosci. 25: 6601-6609. Full Text

Lee, K. W., Y. Kim, & A. M. Kim. 2006. Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc. Nat. Acad. Sci. 103: 3399-3404.

Ryan, X. Z. P., J. Alldritt, P. Svenningsson, et al. 2005. The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology. Neuron 47: 85-100.

Svenningsson, P., K. Chergui, & I. Rachleff. 2006. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311: 77-80.

Connie Cepko

Cepko, C. L. 2005. Effect of gene expression on cone survival in retinitis pigmentosa. Retina 25: S21-S24.

Corbo, J. C. & C. L. Cepko. 2005. A hybrid photoreceptor expressing both rod and cone genes in a mouse model of enhanced s-cone syndrome. PLoS Genet. 1: e11.

Harpavat, S. & C. L. Cepko. 2006. RCAS-RNAi: a loss-of-function method for the developing chick retina. BMC Dev. Biol. 6: 2. Full Text

Jadhav, A. P., H. A. Mason, & C. L. Cepko. 2006. Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development 133: 913-923.

Sen, J., S. Harpavat, M. A. Peters, et al. 2005. Retinoic acid regulates the expression of dorsoventral topographic guidance molecules in the chick retina. Development 132: 5147-5159. Full Text

Reisa Sperling

Chua, E. F., E. Rand-Giovannetti, D. L. Schacter, et al. 2004. Dissociating confidence and accuracy: functional magnetic resonance imaging shows origins of the subjective memory experience. J. Cogn. Neurosci. 16: 1131-1142.

Chua, E. F., D. L. Schacter, E. Rand-Giovannetti, et al. 2006. Understanding metamemory: neural correlates of the cognitive process and subjective level of confidence in recognition memory. Neuroimage 29: 1150-1160.

Dickerson, B. C., D. H. Salat, D. N. Greve, et al. 2005. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65: 404-411.

Dickerson, B. C. & R. A. Sperling. 2005. Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer's disease. NeuroRx. 2: 348-360. Full Text

Rand-Giovannetti, E., E. F. Chua, A. E. Driscoll, et al. 2006. Hippocampal and neocortical activation during repetitive encoding in older persons. Neurobiol. Aging 27: 173-182.

Peter Lansbury

Das, C., Q. Q. Hoang, C. A. Kreinbring, et al. 2006. Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. Proc. Natl. Acad. Sci. 103: 4675-4680.

Lansbury, P. T. 2004. Back to the future: the 'old-fashioned' way to new medications for neurodegeneration. Nat. Med. 10: S51-S57.

Lansbury, P. T. & T. Fagan. 2005. Your health in the 21st century. A fix for faulty proteins. Newsweek 145: 52.

Ray, S. S., R. J. Nowak, R. H. Brown, et al. 2005. Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation. Proc. Natl. Acad. Sci. 102: 3639-3644. Full Text

Rochet, J. C., T. F. Outeiro, K. A. Conway, et al. 2004. Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease. J. Mol. Neurosci. 23: 23-34.

Dale Schenk

Masliah, E., E. Rockenstein, A. Adame, et al. 2005. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46: 857-868.

Masliah, E., L. Hansen, & A. Adame. 2005. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64: 129-131.

Schenk, D. 2004. Hopes remain for an Alzheimer's vaccine. Nature 431: 398.

Thal, L. J., K. Kantarci, E. M. Reiman, et al. 2006. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis. Assoc. Disord. 20: 6-15.

Speakers

Karen Hsiao Ashe, MD, PhD

Unversity of Minnesota Medical School
e-mail | web site | publications

Karen Ashe is a professor in the departments of neurology and neuroscience at the University of Minnesota Medical School, and director of the aging and Alzheimer research laboratory. She led the team that developed the Tg2576 mouse that develops signs of Alzheimer's disease as it ages, thus paving the way for drug research and therapies and promoting a deeper understanding of the disease around the world. The development of the mouse was named one of the Top 10 Medical Advances by Harvard Medical School in 1996. The National Institutes of Health (NIH) hailed the mouse model for its usefulness in testing drugs that affect the disease process, not just those that treat its symptoms.

Ashe received her PhD in developmental neuroanatomy from the Massachusetts Institute of Technology. In 1982, she received her MD from Harvard-MIT Health Sciences and Technology Program. She completed a neurology residency at the University of California, San Francisco.

Robert H. Brown, Jr., MD, PhD

Massachusetts General Hospital
Harvard Medical School
e-mail | web site | publications

Robert Brown is director of the Day Neuromuscular Research Laboratory and the Muscular Dystrophy Association clinic at the Massachusetts General Hospital. He is also professor of neurology at Harvard Medical School.

Brown graduated from Harvard Medical School and completed his doctoral training in neurophysiology at Oxford University. He trained in neurology at the Massachusetts General Hospital. In 1984, Brown founded the Day Neuromuscular Research Laboratory was founded to investigate neuromuscular diseases, including Miyoshi myopathy and Amyotrophic Lateral Sclerosis.

Ted Dawson, MD, PhD

Johns Hopkins University School of Medicine
e-mail | web site | publications

Ted Dawson is the Leonard and Madlyn Abramson Professor in neurodegenerative diseases, director of the neuroregeneration and repair program in the Institute for Cell Engineering, director of the Parkinson's Disease and Movement Disorder Center, and professor of neurology and neuroscience at the Johns Hopkins University School of Medicine.

Many advances in neurobiology of disease have stemmed from his identification of the mechanisms of neuronal cell death and the elucidation of the molecular mechanisms of neurodegeneration. He pioneered the role of nitric oxide in neuronal injury in stroke and excitotoxicity and elucidated the molecular mechanisms by which nitric oxide and poly (ADP-ribose) polymerase kills neurons. His studies of nitric oxide led to major insights into the neurotransmitter functions of this gaseous messenger molecule. Dawson co-discovered the neurotrophic properties of non-immunosuppressant immunophilin ligands. His discoveries have led to innovative approaches and enhanced the development of new agents to treat Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders.

Michael S. Wolfe, PhD

Brigham & Women's Hospital
Harvard Medical School
e-mail | web site | publications

Michael Wolfe is a researcher in the departments of neurology, and biological chemistry and molecular pharmacology at Brigham & Women's Hospital of Harvard Medical School. The Wolfe lab studies intramembrane proteases that play critical roles both in normal biology and in human disease, specifically the chemistry and biology of γ-secretase. Findings from the lab implicate a multi-pass protein called presenilin as the catalytic component of a larger γ-secretase complex. Missense mutations in presenilin are thought to cause hereditary Alzheimer's disease, and these mutations specifically affect γ-secretase activity.

Wolfe received his PhD in medicinal chemistry from the University of Kansas and completed his postdoctoral training in cell biology at the National Institutes of Health. After five years on the faculty at the University of Tennessee, he joined Harvard Medical School as associate professor of neurology in 1999.

Paul Greengard, PhD

The Rockefeller University
e-mail | web site | publications

Paul Greengard is best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson, and Eric Kandel were awarded the Nobel Prize for Physiology or Medicine for their discoveries concerning signal transduction in the nervous system. He is currently Vincent Astor Professor at The Rockefeller University, where his research group focuses on the amyloid precursor protein (APP), the neurobiology of signaling in the brain, and the mechanisms of action of neurotransmitters, therapeutic agents, and drugs of abuse.

Connie Cepko, PhD

Harvard Medical School
e-mail | web site | publications

Connie Cepko is professor of genetics at Harvard Medical School. She received her PhD degree from the Massachusetts Institute of Technology, working with Phillip Sharp on the assembly of the adenovirus capsid. She remained at MIT as a Jane Coffin Childs Fellow in the laboratory of Richard Mulligan, where she helped develop the technology of retrovirus-mediated gene transduction. Cepko is a member of the National Academy of Sciences and is a Howard Hughes Medical Institute investigator.

Cepko and her colleagues study the development of the vertebrate central nervous system, particularly the development of the retina. They are also studying the mechanisms of photoreceptor degeneration, especially as it can occur as a failure of development.

Reisa A. Sperling, MD

Brigham & Women's Hospital
e-mail | web site | publications

Reisa Sperling is the director of clinical research of the memory disorders unit at Brigham & Women's Hospital and an assistant professor of neurology at Harvard Medical School. She is also codirector of the neurology clinical trials service of the Harvard Center for Neurodegeneration and Repair and the director of the neuroimaging subcore of the Massachusetts Alzheimer's Disease Research Center. Finally, she serves as director of the neuroimaging group of the gerontology research unit at Massachusetts General Hospital.

Sperling's research is focused on the early diagnosis and treatment of Alzheimer's disease. Her recent work involves the use of functional MRI to study alterations in brain function during associative memory tasks. She is the principal investigator of the National Institutes of Health and private foundation grants to develop neuroimaging outcome markers for clinical trials and is currently running several clinical trials of novel therapies to treat Alzheimer's disease. She has received the American Academy of the Neurology Clinical Research Fellowship Award, the Harvard Medical School Scholars in Medicine Award, and the Paul Beeson Faculty Scholars in Aging Award.

Peter T. Lansbury, Jr., PhD

Brigham & Women's Hospital
e-mail | web site | publications

Peter Lansbury is professor of neurology in the Center for Neurologic Diseases at Brigham & Womens Hospital. He received his doctorate degree in organic chemistry from Harvard University in 1985, where he worked with Nobel laureate E. J. Corey. After a postdoctoral fellowship with the late Tom Kaiser at The Rockefeller University, he joined the faculty of Massachusetts Institute of Technology as an assistant professor of chemistry in 1988. He moved to his present position in 1996.

Lansbury serves as director of the Brigham & Women's Hospital Morris K. Udall Parkinson's Disease Research Center of Excellence. He is a member of the steering committee of the Harvard Center for Neurodegeneration and Repair and is the cofounder and chair of the laboratory for drug discovery in neurodegeneration. Lansbury serves on the scientific advisory boards of En Vivo Pharmaceuticals, the ALS-Therapy Development Foundation, and the Boston Cure Project for Multiple Sclerosis. He also serves on the editorial board of the Journal of Molecular Biology and on the board of directors of the Parkinson's Action Network.

Dale Schenk, PhD

Elan Corporation
e-mail | web site | publications

Dale Schenk is senior vice president and chief scientific officer of the Elan Corporation, a neuroscience-based biotechnology company. Schenk has been a key figure in contributing to Elan's progress in Alzheimer's disease and is internationally recognized for his contributions to the field, particularly as the inventor of β-amyloid immunotherapy. Schenk has also served as senior vice president of discovery research at Elan, and as the company's vice president of neurobiology.

Previously, Schenk was director of neurobiology for Athena Neurosciences, until the company was acquired by Elan. Earlier at Athena, he served as the leader of the anti-α4 integrin monoclonal antibody project team, as director of immunochemistry, and as senior scientist and project leader for the Alzheimer's disease diagnostic program.


Adrian Ivinson

Adrian Ivinson is director of the Harvard Center for Neurodegeneration & Repair.