Saturday, July 5, 2008

ALS toxic assault

ALS toxic assault
Date: 07/04/2008
Align Center
Leaky blood vessels that lose their ability to protect the spinal cord from toxins may play a role in the development of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, according to research published in the April issue of Nature Neuroscience.
The results mark the first time that scientists have witnessed molecular changes occurring long before key nerve cells start dying. The unexpected finding opens up a new front in studies of ALS, a disease in which motor neurons in the spinal cord die off for unknown reasons, resulting in dramatically weakened muscles. Patients lose their strength, their ability to move or swallow, and eventually lose their ability even to breathe. Most patients live only a few years after diagnosis.
"We believe these changes contribute to or possibly initiate the onset of ALS," said lead author Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center. "It's clear that these changes occur before the loss of neurons, and it's well known that the types of changes we are seeing certainly injure or kill these types of cells, which are extremely sensitive to their biochemical environment."
The results, discovered by studying mutant mice that have an inherited form of the disease, were made by a collaboration of neuroscientists from the University of Rochester Medical Center working together with a team of ALS experts from the University of California at San Diego. Zlokovic, a pioneer in learning how the body's vascular system plays a role in neurodegenerative diseases like Alzheimer's disease and ALS, led the team, and the first author is post-doctoral researcher Zhihui Zhong, Ph.D.
While it's unlikely the new findings will help ALS patients immediately, the results open up a new and unexpected way to think about the disease. Zlokovic's team is currently testing in the laboratory a compound that may help seal up leaky vessels and protect the neurons targeted by ALS.
The team studied mice with a mutation in a gene for superoxide dismutase 1 (SOD-1), which in healthy people and mice plays an important role keeping cells safe from damaging molecules known as free radicals. Scientists estimate that SOD-1 mutations play a role in a small number of cases of ALS overall in people, about one-quarter of the 10 percent or so of cases that are inherited. But those cases provide a unique window to study the disease's initial steps.
In the Nature Neuroscience paper, the group from Rochester's Center for Neurodegenerative and Vascular Brain Disorders and UCSD showed that a breakdown in the natural barrier between the blood and the spinal cord breaks down early on in mice destined to get ALS, long before nerve cells appear sick or die.
In this work, the team showed that the barrier between the blood and the spinal cord weakens in all three types of genetically based ALS cases that involve SOD-1 mutations, allowing toxic substances to flood into the spinal cord and directly affect neurons.
That barrier is crucial for the health of our central nervous system, which is treated like the inner sanctum of the body. Like a high-performance race car that demands a choice fuel, our neurons work well only if the chemical environment in the brain and spinal cord is precisely maintained within a strict, narrow set of conditions.
To maintain that select environment, the body has strict barriers or gateways for substances entering or exiting the central nervous system. Blood vessels run through our brain and spinal cord and supply oxygen and other nutrients, and the lining of those blood vessels constitutes a biochemical barrier to protect the central nervous system from toxins, inflammatory cells, red blood cells, blood products, and a variety of other potential toxic insults.
The barrier between the blood and the spinal cord isn't some stand-alone structure that keeps all substances away from the spinal cord. Rather, the word "barrier" describes an elaborate molecular lattice that lines the insides of the blood vessels that weave throughout the spinal cord. The lattice controls which molecules can cross from the blood to the neurons in the spinal cord, and which cannot. It's a bit like netting with very small openings that line the inside of blood vessels.
Oxygen and many nutrients get the OK to pass through the barrier in measured amounts. And the barrier readily accepts waste products from the spinal cord, transporting them away from the central nervous system and eventually out of the body. But the "netting" should be taut and should bar substances in the blood that have no business being near neurons.
The team found that a SOD-1 mutation disrupted key building blocks in the barrier. Essentially, the mutations loosened the lattice, creating bigger holes in the barrier that allowed molecular interlopers to pass from the blood to the spinal cord.
Mice with the mutation had lower levels of three types of "tight junction proteins" that are key components of the barrier: ZO-1, occludin and claudin-5. In mice just two months old, the numbers of those important tight junction proteins in the linings of blood vessels were reduced by about half, by 40 to 60 percent, allowing the lattice to loosen abnormally.
The weakened barrier brought about several problems. Neurons were exposed directly to biochemical byproducts of haemoglobin, which forms reactive oxygen molecules that injure neurons. Where the barrier had weakened, tiny hemorrhages dotted the spinal column. The smallest blood vessels crucial to nerve health shrunk: Mice with the mutation had total capillary length in the spinal cord 10 to 15 percent less than healthy mice, and their blood flow in the spinal cord was reduced by 30 to 45 percent.
Scientists must investigate whether the same processes happen in forms of ALS that are not inherited. Zlokovic notes that from what is known so far, the disease progresses exactly in inherited forms and forms that are not inherited.
"The vascular system is crucial to health - it's how oxygen and other nutrients are delivered to cells, and how toxins are removed," said Zlokovic, who is professor of Neurosurgery and Neurology and director of the Center for Neurodegenerative and Vascular Brain Disorders. "Any damage to the vascular system is a serious threat to the organism. It's clear now that the vascular system is certainly involved in the development of ALS."
Zlokovic first began doing research on the disease in 2004, when a former classmate from medical school who had been diagnosed with ALS and was looking for new treatments contacted him. By the time his friend died two years later, Zlokovic was well underway in studies investigating the possible role of the vascular system.
During the last 15 years, Zlokovic has pioneered the view that the vascular system plays a central role in many neurodegenerative diseases. He has found that a breakdown in the barriers between the blood and the central nervous system may be at the root of diseases like Alzheimer's. In January, Zlokovic reviewed the evidence for involvement of the barrier in diseases like Alzheimer's, ALS, and multiple sclerosis in a 24-page review in Neuron.

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