Medicine@Yale publication

May/June 2008   Volume 4 Issue 2

YSM Home Page | Medicine@Yale

Inside this issue

Cover stories

Smoothing the road

It's only rock 'n' roll, but it supports cancer research

Cartoonist's work on wartime trauma garners award

Partnerships

After heartbreak, a commitment to make a difference

Grants & contracts

People

Lifelines: David J. Leffell

Yale geneticist wins Wiley Prize

Expert on myeloma to head hematology

Out & about

Science

A scientific assault on brain diseases

Advances: A two-pronged tactic to grow new bone | Sloppy gene repairs: a cause of lymphoma?

Health

A 'reluctant honoree' receives his due at last

Advances: Taking a bite out of stroke | Age no barrier for heart bypass surgery

Education

A match made in medical school

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A scientific assault on brain diseases

Program to unravel Alzheimer’s, Parkinson’s gears up for a tough battle

Primary and affiliated faculty in the medical school’s Program in Cellular Neuroscience, Neurodegeneration and Repair include (back row, from left) Anthony Koleske, Thomas Biederer, (middle row, from left) David McCormick, Sreeganga Chandra, Co-Director Stephen Strittmatter, (front row, from left) Susumu Tomita, Marina Picciotto, Co-Director Pietro De Camilli and David Zenisek.

The School of Medicine is home to outstanding research programs in cell biology and neurobiology, and members of its faculty have made major contributions to our understanding of how nerve cells are organized and function in the brain. However, despite strong clinical programs in Alzheimer’s disease and other age-related disorders, up until a few years ago there was surprisingly little basic research at the medical school on the growing problem of neurodegenerative disease, and little effort to translate new insights into badly needed therapies.

To remedy that deficiency, the medical school called on two members of Yale’s Kavli Institute for Neuroscience, Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology, and Pietro De Camilli, M.D., the Higgins Trust Professor of Cell Biology and Howard Hughes Medical Institute Investigator, to create and direct a new Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR). The CNNR program, launched in 2006, has expanded the reach of cellular neuroscience at the School of Medicine from learning how healthy nerve cells work to understanding what goes wrong in disease.

During brain development, nerve cells send out long extensions, known as axons, that seek out and make contact with other nerve cells at specialized sites called synapses. In the normal adult brain, these connections form a network in which electrical signals are sent along axons to synapses, where they are converted to a chemical signal that passes the neural “message” on to other cells. Neurodegenerative diseases, stroke and spinal cord injuries cause damage to axons, synapses or both, and the complementary research interests of the CNNR program’s codirectors—Strittmatter is an expert on axon growth; De Camilli is a pioneering researcher in synapse formation and function—drive the center’s comprehensive approach to nervous system diseases.

Strittmatter’s research group has discovered that NOGO, a protein in the fatty myelin sheaths that insulate nerve cell axons prevents axons from seeking further connections in the adult brain. This helps to solidify neural circuits, but NOGO also blocks axon growth after spinal cord injury and stroke, keeping the brain from repairing itself. Strittmatter and his colleagues are exploring ways to block NOGO’s action to encourage the sprouting of axons and reconnection of nerve tracts before injury or disease cause permanent damage.

In many neurodegenerative diseases, a loss of synaptic connections between cells appears as one of the first signs of trouble. De Camilli has increased our understanding of how chemical neurotransmitters, which are packaged into spherical packets known as synaptic vesicles, are released into the synapse. Using biochemical and genetic techniques combined with light and electron microscopy, De Camilli is elucidating mechanisms underlying the formation and traffic of synaptic vesicles within axon terminals and unveiling how these mechanisms might be compromised in neurodegenerative diseases. The CNNR program’s first recruit, Assistant Professor of Neurology Sreeganga S. Chandra, Ph.D., is also a specialist on the synpase. Chandra is studying the synuclein family of synaptic proteins, one of which malfunctions in Parkinson’s disease.

The CNNR program has drawn in prominent scientists from other departments as affiliated faculty:

• Cellular & Molecular Physiology: Susumu Tomita, Ph.D., whose studies on the role of the excitatory neurotransmitter glutamate may produce new insights into Alzheimer’s and Parkinson’s diseases, and David Zenisek, Ph.D., A scientific assault on brain diseases who studies how vesicles transport and release neurotransmitters into the synapse, as well as how neurotransmitters are “recycled” by being gathered up from the synapse in newly formed vesicles;
• Genetics: Arthur Horwich, M.D., Ph.D., a widely recognized authority on protein folding who has recently turned his attention to the misfolded proteins that are characteristics of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease);
• Molecular Biophysics and Biochemistry: Thomas Biederer, Ph.D., who studies the development of synapses and how deficits in synapse formation may cause neurodegenerative diseases, and Anthony Koleske, Ph.D., who is seeking ways to prevent dendrite regression, an early hallmark of Alzheimer’s disease;
• Neurobiology: David A. McCormick, Ph.D., an expert on neural electrophysiological function from the cellular to the network level;
• Pharmacology: Ya Ha, Ph.D., who is solving the molecular structure of the enzymes that produce the neurotoxic amyloid beta peptide, a known culprit in Alzheimer’s disease;
• Psychiatry: Angus Nairn, Ph.D., studies the neurotransmitter dopamine, which is disrupted in Huntington’s and Parkinson’s diseases. Marina Picciotto, Ph.D., works on nicotinic acetylcholine receptors, proteins involved in memory, which may reveal new drug targets for Alzheimer’s.

By linking with each other and with primary members of the CNNR program, these investigators will gain practical help from one another as well as a broader context for their work on neurodegenerative diseases. “While the main goal of the CNNR program is to advance knowledge about diseases,” De Camilli points out, “studies of diseases will also help improve our understanding of normal nervous system function.”

The medical school’s Boyer Center for Molecular Medicine is the CNNR program’s new home. Thanks to generous donors, core facilities for cell imaging, genomics and electrophysiology are in the works. With a plan to hire at least five more new faculty members, the program is ready to take off, according to Strittmatter.

“A few years ago, research on neurodegenerative disease at Yale was hit or miss, confined to corners of scattered departments, with no organization and fairly minor activity,” Strittmatter says. “We have already changed that, and over the next few years, we plan to change it more.”