Degenerative Diseases

Disarming the botulinum neurotoxin

by Heather Buschman on February 23, 2012 at 11:01 am | 1 comment

Rongsheng Jin, Ph.D., assistant professor at Sanford-Burnham

Researchers at Sanford-Burnham Medical Research Institute and collaborators at the Medical School of Hannover in Germany recently discovered how the botulinum neurotoxin, a potential bioterrorism agent, survives the hostile environment in the stomach on its journey through the human body. Their study, published February 24 in Science, reveals the first 3D structure of a neurotoxin together with its bodyguard, a protein made simultaneously in the same bacterium. The bodyguard keeps the toxin safe through the gut, then lets go as the toxin enters the bloodstream. This new information also reveals the toxin’s weak spot—a point in the process that can be targeted with new therapeutics.

“Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it,” said Rongsheng Jin, Ph.D., assistant professor in Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study.

Unusual alliances enable movement

by Guest Blogger on February 9, 2012 at 6:57 am | 1 comment

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Rongsheng Jin, Ph.D (second from the right) and researchers in his laboratory

provided by Georgia Health Sciences University

Some unusual alliances are necessary for you to wiggle your fingers, researchers report.

Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Lin Mei, Ph.D., director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University.

During development, neurons in the spinal cord reach out to muscle fibers to form a direct line of communication called the neuromuscular junction. Once complete, motor neurons send chemical messengers, called acetylcholine, via that junction so you can text, walk, or breathe.

Two Sanford-Burnham researchers named AAAS Fellows

by Communications Staff on December 23, 2011 at 6:00 am | 0 Comments

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Dr. John Reed and Dr. Stuart Lipton

Sanford-Burnham is a highly collaborative institute, embracing opportunities to connect with scientists nationwide, so perhaps the greatest honor our researchers can receive is the recognition of their peers. Our CEO John C. Reed, M.D., Ph.D., and Director of our Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Stuart A. Lipton, M.D., Ph.D., have been named as Fellows of the American Association for the Advancement of Science (AAAS). Fellows are recognized for meritorious efforts to advance science or its applications. This year’s honorees were formally announced today in the AAAS News & Notes section of the journal Science.

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Using stem cells to treat Parkinson’s disease

by Heather Buschman on September 26, 2011 at 7:13 am | 0 Comments

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Neurons derived from embryonic stem cells

When neurons that make a chemical called dopamine are slowly destroyed, nerve cells in that part of the brain cannot properly send the messages that would normally control muscle function. As the damage gets worse with time, a person experiences tremors and movement becomes difficult. This is Parkinson’s disease.

In short, Parkinson’s patients need more dopamine. Or, better yet, new neurons that produce dopamine on their own. In a paper published August 25 in the journal PLoS ONE, a team led by Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center, demonstrates how this therapeutic approach might be possible.

Autophagy 101

by Bruce Lieberman on September 5, 2011 at 7:34 am | 0 Comments

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An autophagosome full of degraded old cell parts, as viewed under an electron microscope. (Image by Malcolm Woods, The Scripps Research Institute)

Every well-run house needs someone to clean up the clutter, prune the hedges, and rake up the leaves, even whip up something to eat when the refrigerator is empty. In the life of a cell, those kinds of jobs are handled by an incredible process called autophagy.

Biologists first observed autophagy in the early 1960s as a mechanism by which cells break down their own components and recycle the parts. Autophagy, which literally means “to eat oneself,” is essential to cell survival, particularly when food is scarce.

But there’s a much larger role for autophagy than just helping a cell survive starvation. The process helps cells dispose of malfunctioning parts, clean up clutter, and defend against invading pathogens.

How to make to new neurons

by Bruce Lieberman on August 31, 2011 at 9:55 am | 0 Comments

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Neurons (Image courtesy of the Lipton lab)

Imagine the ability to take skin cells from a patient with Alzheimer’s disease, convert them directly into brain cells, and then study how the disease progresses in those cells—which still contain the patient’s DNA—all in the lab, with minimal invasiveness on the part of the patient. Then imagine taking those same brain cells and testing novel but risky drugs that could cure the devastating disease—again, in the safety of a dish in the lab.

Researchers are on their way to achieving this remarkable milestone. Dr. Stuart Lipton at Sanford-Burnham, Dr. Sheng Ding at the Gladstone Institutes, and their collaborators recently figured out how to reprogram skin cells directly into functioning neurons. The study was published online July 28 in the journal Cell Stem Cell.

“This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days, rather than the months required previously,” Dr. Lipton says in a statement released by the Gladstone Institutes.

The paper is one of several recent studies that are all zeroing in on a long-sought-after advance in stem cell science: the potential to obtain unlimited numbers of brain cells from an easily accessible tissue such as the skin.

Developments to Watch: New frontier in Alzheimer’s disease

by Communications Staff on August 24, 2011 at 10:26 am | 0 Comments

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Dr. Evan Snyder (right) interviews Dr. Stuart Lipton in Medscape's "Developments to Watch"

Medscape, a physician-oriented website run by WebMD, visited Sanford-Burnham’s La Jolla campus this summer to record interviews with researchers from both Orlando and San Diego for a new online video program called Developments to Watch. The talk show-like discussions are hosted by Dr. Evan Snyder, who directs the Stem Cells and Regenerative Biology Program at Sanford-Burnham. The first episode, A New Frontier in Alzheimer’s Disease, is now available. In the video, Dr. Snyder speaks with Dr. Stuart Lipton, director of the Del E. Web Neuroscience, Aging and Stem Cell Research Center, about his work on Alzheimer’s disease. They discuss what new findings—and potential treatments—are on the horizon and how they might impact patients.

A user name and password are required to access Medscape, but the site and content are free. New installments will be added monthly.

Watch the video, then come back here to let us know what you think!

For more about our research on Alzheimer’s disease, check out these blog posts:
Getting to the root of Alzheimer’s disease
Diagnosing Alzheimer’s Earlier
New Partnership Targets Brain Conditions
Safely Treating Alzheimer’s Disease
Saying NO to Alzheimer’s and Parkinson’s Diseases

Getting to the root of Alzheimer’s disease

by Heather Buschman on August 17, 2011 at 5:47 am | 0 Comments

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Dr. Stuart Lipton

Alzheimer’s disease is characterized by abnormal proteins that stick together in little globs, disrupting cognitive function (thinking, learning, and memory). These sticky proteins are mostly made up of beta-amyloid peptide. A better understanding of these proteins, how they form, and how they affect brain function will no doubt improve the diagnosis and treatment of Alzheimer’s disease. To this end, a research team led by Dr. Stuart Lipton‘s group found that beta-amyloid-induced destruction of synapses—the connections that mediate communication between nerve cells—is driven by a chemical modification to an enzyme called Cdk5. The team found that this altered form of Cdk5 (SNO-Cdk5) was prevalent in human Alzheimer’s disease brains, but not in normal brains. These results, published August 15 in the Proceedings of the National Academy of Sciences of the USA, suggest that SNO-Cdk5 could be targeted for the development of new Alzheimer’s disease therapies.

Cdk5 is an enzyme known to play a role in normal neuronal survival and migration. In this study, Dr. Lipton and colleagues found that beta-amyloid peptides, the hallmark of Alzheimer’s disease, trigger Cdk5 modification by a chemical process called S-nitrosylation. In this reaction, nitric oxide (NO) is attached to the enzyme, producing SNO-Cdk5 and disrupting its normal activity.

Serendipity in science

by Faculty Contributor on July 28, 2011 at 12:46 pm | 0 Comments

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Stephen Hawking, famous English physicist, lives with amyotrophic lateral sclerosis (Lou Gehrig's disease), a debilitating disese that affects motor neurons.

Many people are familiar with the story of Alexander Fleming’s accidental discovery of penicillin produced by mold growing in a bacterial culture. These same people would probably be surprised at how often carefully planned scientific experiments yield unexpected (and even unwanted!) results, usually leading to repetition of the experiment to discover where things went wrong. However, one mark of a really good investigator (like Fleming) is the ability to recognize when the “error” may actually be a truth that provides a key new insight. The phenomenon of looking for one thing and serendipitously finding another plays a surprisingly frequent role in the process of scientific discovery.

A case in point can be found in studies of motor neuron degeneration being carried out in the laboratory of Dr. Dongxian Zhang, associate professor at Sanford-Burnham. The death of motor neurons in the spinal cord is responsible for lethal diseases such as spinal muscular atrophy and amyotropic lateral sclerosis (Lou Gehrig’s disease), neither of which is treatable or curable. Dr. Zhang’s group hypothesized that motor neuron death might be caused by the absence or malfunction of a specific type of membrane receptor called MNR. To test their theory more directly, they paid a commercial company to create a mouse in which MNR was genetically deleted. Sure enough, motor neurons in these mice degenerated a few days after birth. To further prove their point, the group attempted to rescue the lethal defect by genetically adding back the MNR gene. To their consternation, these transgenic rescue mice still died shortly after birth.

“At that point we were completely stumped and discouraged,” confesses Dr. Zhang.

Renowned biochemist joins Sanford-Burnham

by Kristina Meek on July 19, 2011 at 3:01 pm | 0 Comments

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Dr. Randal J. Kaufman

This month we welcomed Sanford-Burnham’s newest faculty member, Dr. Randal J. Kaufman. Dr. Kaufman joins the Institute as professor and director of the Degenerative Disease Research Program, in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center.

“I am looking forward to the opportunities for collaboration that Sanford-Burnham affords,” Dr. Kaufman says. “This promises to be a very productive environment for my area of research.”

Dr. Kaufman’s current research is focused on understanding the fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded proteins within the endoplasmic reticulum (ER). When proteins fail to fold correctly, they don’t work properly. Certain types of misfolded proteins defy eradication by the cellular protein degradation machinery and accumulate with age, causing cellular toxicity. In many degenerative diseases, including neurological, metabolic, genetic and inflammatory diseases, it’s thought that the accumulation of misfolded proteins leads to cellular dysfunction and death.

Join us for a congressional briefing on Alzheimer’s disease

by Heather Buschman on July 8, 2011 at 3:25 pm | 1 comment

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The United States Capitol, Washington, D.C.

What: Congressional Briefing on Alzheimer’s Disease Research and Therapeutic Advancements, Innovations and Treatments

CHI-The California Healthcare Institute and the Healthcare Institute of New Jersey (HINJ) invite you to a congressional briefing that will facilitate a dialogue about Alzheimer’s disease research. This program will include an overview of advances stemming from California’s and New Jersey’s life sciences sectors, with an expert panel discussing current research and drug development, as well as future discoveries, followed by a brief question and answer session.

When: July 14, 2011, 9:30 a.m. – 11 a.m.
Where: Capitol Visitor’s Center, Congressional Meeting Room South, Washington, D.C.

Why: According to a 2011 report released by the Alzheimer’s Association, an estimated 5.4 million people are living with Alzheimer’s disease, and someone develops the disease every 69 seconds. The United States, like many other countries, has an aging population with nearly one in five residents reaching the age of 65 or older by 2030. Additionally, in 2010, 14.9 million family members and friends provided 17 billion hours of unpaid care to those living with Alzheimer’s and other dementias — care valued at approximately $202 billion. With the imminent increase in dementia caused by Alzheimer’s disease and other conditions — and without a cure — the development of new innovations and treatments remains all the more critical to assist in improving the quality of life for those affected. CHI members Genentech, Pfizer, Sanford-Burnham and University of California, Irvine and HINJ members Merck, Lundbeck, Bayer and Pfizer are all working to advance important new studies and therapeutics.

Who:
Rep. Chris Smith (R-NJ)
Rep. Linda Sanchez (D-CA)

David Gollaher, Ph.D., President & CEO, CHI
Dean J. Paranicas, President & CEO, HealthCare Institute of New Jersey (HINJ)
Joseph Hammang, Ph.D., Senior Director, Worldwide Science Policy, Pfizer
Stuart Lipton, M.D., Ph.D., Director, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute
Bob Nelson, Ph.D., Research Fellow, Lundbeck Research USA
Wayne Poon, Ph.D., Director, UCI MIND Brain Bank and Tissue Repository
Kimberly Scearce-Levie, Ph.D., head of in vivo neurobiology at Genentech Inc.

RSVP to Caitlin Doyle at doyle@chi.org or (202) 974-6323

Coming soon: Medscape’s “Developments to Watch”

by Kristina Meek on July 1, 2011 at 7:08 am | 0 Comments

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Dr. Evan Snyder (right) interviews his colleague, Dr. Steven Smith, on the Medscape set.

Dr. Evan Snyder interviews his colleague, Dr. Steven Smith, on the Medscape set.

Last week, Sanford-Burnham’s Fishman Auditorium, on the Institute’s La Jolla campus, was transformed into a temporary television studio. It was hardly recognizable under the bright lights and set dressing. Medical website Medscape recorded interviews with three Sanford-Burnham researchers for a new video series called “Developments to Watch.” The talk show-like discussions were hosted by Dr. Evan Snyder, who directs the Stem Cells and Regenerative Biology Program at Sanford-Burnham. Dr. Snyder is both a medical doctor who regularly sees patients and a scientist who conducts research in his own lab – the perfect person to help explain how discoveries made today might one day help patients.

Medscape is part of the network of sites run by WebMD. With this newest video series, Sanford-Burnham scientists will be providing expert commentary and information to help keep Medscape’s audience – primary care physicians, specialists and other health professionals – up-to-date on the latest medical research and what it means for their patients.

Diagnosing Alzheimer’s Earlier

by Amelia Tomas on April 27, 2011 at 9:59 am | 0 Comments

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Dr. Stuart Lipton

For the first time in nearly 30 years, new criteria will guide the diagnosis of Alzheimer’s disease. The current approach focuses on an individual’s cognitive decline – primarily thinking, learning and memory. But new research has shown that changes in the brain happen long before these symptoms emerge, perhaps even decades earlier.The new guidelines, issued in April by the National Institute on Aging and the Alzheimer’s Association, spotlight the disease’s progression from its earliest onset (molecular changes in the brain). The goal is to detect the disease faster in at-risk patients. As research advances, these new diagnostic tools could allow doctors to treat patients proactively to prevent the emergence of physical symptoms.

“These guidelines should help us diagnose Alzheimer’s earlier, which eventually will be very important as new treatments for early intervention are developed,” stated Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center. Dr. Lipton is also a neurologist who sees many Alzheimer’s disease patients in his own clinical practice and is credited with developing memantine (marketed in the United States as Namenda®), the latest FDA-approved Alzheimer’s drug.

New Partnership Targets Brain Conditions

by Josh Baxt on January 18, 2011 at 9:27 am | 1 comment

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Robots in the Prebys Center screen hundreds of thousands of compounds to find the handful that could become new medicines.

Sanford-Burnham has been conducting cutting-edge research on neurological and neuropsychiatric conditions for many years and recently that research received a big boost. The Institute announced a collaboration with Ortho-McNeil-Janssen Pharmaceuticals, Inc., (OMJPI), a division of Johnson & Johnson, to discover new drugs to treat Alzheimer’s diseaseand major psychiatric disorders.Under the agreement, Sanford-Burnham will look for new therapeutic targets for Alzheimer’s disease and neuropsychiatric conditions. Then, the Conrad Prebys Center for Chemical Genomics (Prebys Center) will identify chemical compounds that therapeutically alter those targets. These compounds will then be optimized and directed into OMJPI’s drug pipeline.

Mitochondria 101

by Heather Buschman on December 3, 2010 at 7:24 am | 5 Comments

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Cartoon diagram of a mitochondrion, peeled back to reveal the inner membrane and inner workings of the cell's "powerhouse". (Image courtesy of Wikimedia Commons)

Cartoon diagram of a mitochondrion, the "powerhouse" of the cell. (Image courtesy of Wikimedia Commons)

“In the depths of history, a free-living bacterium was engulfed by a larger cell and was neither digested nor destroyed. Instead, it was domesticated. It forged a unique and fateful partnership with its host, eventually becoming the mitochondria of today.” – Ed Yong, Not Exactly Rocket Science, Discover Magazine

Mitochondria are the parts of our cells that we often call the “powerhouse.” Without them, animal cells wouldn’t have the energy they need to sustain life. A mitochondrion is surrounded by two membrane layers, kind of like a little pillow encased in two pillowcases. The inner pillowcase is where most of the action takes place. It’s ruffled, which provides more surface area for the series of chemical reactions that generate ATP, the cell’s currency. Like money, you have to have ATP in order to do things. Cells can cash in ATP to divide, make new proteins, process cellular waste, store fat or do anything else they need to survive (see DNA 101 and Proteins 101).

Because of their role in maintaining a cell’s fuel and energy balance, mitochondria are the subject of intense scrutiny by scientists interested in the molecular underpinnings of metabolism, obesity, diabetes and cancer. But mitochondria also play a role in cell death. Some cells are long-lived (like neurons in the brain), while others turn over quickly (think skin cells). Either way, the process of cellular suicide – called apoptosis – has to be carefully managed in order to both avoid untimely demise and prevent cells from living too long. When called upon, mitochondrial proteins leak out through the outer membrane and into the cell’s cytosol, where they remove the molecular brakes that normally promote survival and activate caspases, enzymes that execute apoptosis. When mitochondrial function or apoptosis go awry, disease can develop – too much cell death causes neurodegenerative diseases like Alzheimer’s, while too little allows cancer cells to avoid destruction.

Top Stories - Degenerative Diseases

Disarming the botulinum neurotoxin

Unusual alliances enable movement

Two Sanford-Burnham researchers named AAAS Fellows

Using stem cells to treat Parkinson’s disease

Autophagy 101

How to make to new neurons

Developments to Watch: New frontier in Alzheimer’s disease

Getting to the root of Alzheimer’s disease

Serendipity in science

Renowned biochemist joins Sanford-Burnham

Join us for a congressional briefing on Alzheimer’s disease

Coming soon: Medscape’s “Developments to Watch”

Diagnosing Alzheimer’s Earlier

New Partnership Targets Brain Conditions

Mitochondria 101

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