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.