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Blood-spinal Cord Barrier Compromised In Mice With ALS

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Old 11-27-2007, 09:17 AM   #1
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Post Blood-spinal Cord Barrier Compromised In Mice With ALS

In the cervical spinal cord, EB was clearly detected within the blood vessels (red, arrowheads) in the control C57BL/6J mice at (A, B, C) 12–13 weeks of age or (D, E) in the lumen of vessels (brilliant green) at 19–20 weeks of age. In G93A mice, vascular leakage of EB (red, arrows) was detected (F, G) at early (13 weeks of age) disease symptoms and (H, I, J) at end-stage of disease (17–18 weeks of age) when more EB extravasation was seen. Arrowheads in F and I indicate vessel permeability. Scale bar in A–J is 25 µm. (Credit: Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, et al, Image courtesy of PLoS One)

ScienceDaily (Nov. 27, 2007) — The blood-spinal cord barrier is functionally impaired in areas of motor neuron damage in mice modeling amyotrophic lateral sclerosis (ALS), report researchers at the University of South Florida Center for Aging and Brain Repair. The barrier disruption was found in mice at both early and late stages of ALS, a progressive neurodegenerative disease affecting nerve cells in the brain and the spinal cord.

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) control the exchange of substances between the blood and the central nervous system. These barriers, formed by cells lining the blood vessels in the brain and the spinal cord, protect nerve cells by restricting entry of potentially harmful substances and cells of the immune system. Impairment in cellular machinery of the BBB and BSCB may lead to a barrier breakdown in many brain and spinal cord diseases or injuries.

"We detected vascular leakage in the cervical and lumbar spinal cord microvessels of ALS mice not only at the end-stage of disease but also in those with early disease symptoms," said lead author Svitlana Garbuzova-Davis, PhD, DSc, assistant professor in the USF Center for Aging and Brain Repair. "This may suggest that large molecules such as the antibody IgG and other blood proteins appear in the spinal cord due to vascular leakage, one possible mechanism accelerating motor neuron damage."

However, Dr. Garbuzova-Davis said, questions remain: "Is the BCSB altered before disease symptoms and other pathological processes begin in ALS, and does the protective barrier's breakdown play a primary role in the development of ALS?"

"If this finding translates to ALS patients, then it should yield important ways of developing new treatments that focus on drugs or cell therapies designed to repair the BSCB," said Paul R. Sanberg, PhD, DSc, co-author and director of the USF Center for Aging and Brain Repair.

The research builds upon another USF study published earlier this year in the journal Brain Research. Using electron microscopy to examine the capillary structure of the BBB and BSCB, the researchers demonstrated extracellular edema and physical damage to capillary endothelial cells, motor neurons, and astrocytes surrounding vessels in mice with early and late ALS symptoms.

In the most recent study, the researchers examined the functional competence of the BSCB in ALS mice. They intravenously injected a blue dye tracer into mice in different stages of ALS. Vascular leakage of the dye was found in mice with initial signs of ALS such a tremor, weight loss and reduced hindlimb extension and in mice with complete hindlimb paralysis at the terminal stage of ALS. Furthermore, the study found decreased expression of the glucose transporter Glut-1 and immunological markers CD146 for endothelial cells and GFAP for astrocytes, which may relate to vascular leakage.

The USF researchers plan to investigate whether the BSCB and BBB are altered in patients suffering from ALS.

Citation: Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, et al (2007) Evidence of Compromised Blood-Spinal Cord Barrier in Early and Late Symptomatic SOD1 Mice Modeling ALS. PLoS One 2(11): e1205. doi:10.1371/journal.pone.0001205

Adapted from materials provided by Public Library of Science.


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Old 11-27-2007, 09:32 AM   #2
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Post A mutation named Magellan steers nerve cells off course

[IMG]Motor nerves growing toward their muscle targets are detected with fluorescent protein in transgenic mouse embryos. A normal (wild type) embryo is shown in green and different mutants isolated in a genetic screen are shown in yellow (Columbus), red (Magellan), and blue (DeLeon). A variety of motor neurone growth and development defects are apparent in the mutants. Photos: © Dr Joe Lewcock, Salk Institute for Biological Studies[/IMG]
A mutation named Magellan steers nerve cells off course
Science Centric
— 26 November 2007 | 22:27 GMT

Newly launched nerve cells in a growing embryo must chart their course to distant destinations, and many of the means they use to navigate have yet to surface. In a study published in the current issue of the journal Neuron, scientists at the Salk Institute for Biological Studies have recovered a key signal that guides motor neurones — the nascent cells that extend from the spinal cord and must find their way down the length of limbs such as arms, wings and legs.

The Salk study, led by Samuel Pfaff, PhD, a professor in the Gene Expression Laboratory, identifies a mutation they christened Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe. The Magellan mutation occurs in a gene that normally pilots motor neurones on the correct course employing a newly discovered mechanism, their results demonstrate.

In the mutants, growing neurones can be seen leaving the spinal cord normally but then appear to lose direction. The elongating cells develop ‘kinks’ and sometimes fold back on themselves or become entwined in a spiral, forming coils outside the spinal cord. ‘They appear to become lost in a traffic roundabout,’ described Pfaff, who observed the growing neurones with fluorescent technology.

Understanding how motor neurones reach the appropriate targets is necessary for the implementation of novel therapies, including embryonic stem cell replacement for the treatment of presently incurable disorders such as Lou Gehrig’s disease, in which motor neurones undergo irreversible decay.

‘Embryonic studies provide useful insights on how to replicate the system in an adult,’ said Pfaff. And, as he also pointed out, the mechanisms used by motor neurones are likely to be similar to those used in other parts of the central nervous system, such as the brain. The Magellan mutation discovered by Pfaff’s group was found in mice, but the affected gene, called Phr1, has also been identified in other model systems, including fruit flies and the worm species C. elegans.

A growing nerve bears at its bow a structure called the growth cone, a region rich in the receptor molecules whose job is to receive cues from the environment, much as ancient mariners who observed the stars and set their course accordingly. During development, the growth cone continuously pushes forward, while the lengthening neurone behind it matures into the part of the cell called the axon. Once the growing cell ‘lands’ at its target in a muscle cell, it is the axon that will relay the messages that allow an animal to control and move its limbs at will.

In Magellan mutants, Pfaff’s team discovered that the growth cone becomes disordered. Rather than forming a distinct ‘cap’ on the developing neurone, the cone is dispersed in pieces along both the forward end and the axon extending behind it.

‘The defect is found in the structure of the neurone itself,’ said Pfaff, noting that the fundamental pieces, such as the receptors capable of reading cues, all seem to be present. Without the correct orientation of receptors, however, signals cannot be read accurately, resulting in growth going off course.

‘A precise gradient normally exists across the cone,’ said Pfaff, ‘which is disrupted in the Magellan mutants.’ As a result, cells lose their polarity. They literally do not know the front end from the back end, according to Pfaff. This sense of polarity is a universal feature common to all growing neurones. Therefore, ‘Phr1 is likely to play a role in most growing neurones to ensure their structure is retained at the same time they are growing larger,’ he said.

Pffaf and his group identified Magellan using a novel system they had developed, in which individual motor neurones and axons can be visualised fluorescently. They were able to screen more than a quarter of a million mutations, and the mutations of interest were rapidly mapped to known genes as a result of the availability of the sequenced mouse genome — a byproduct of the effort to sequence entire genomes such as that in the human.

The Magellan mutation is located in a gene known as Phr1, which is also active in other parts of the nervous system, indicating that it most likely functions to steer other types of neurones, such as those that enervate sensory organs or connect different regions of the brain. Studies of Magellan may therefore shed light on how a variety of neurological disorders might be treated with cell replacement strategies.

Lead author on the study is Joseph W. Lewcock, formerly a postdoctoral fellow in Pfaff’s laboratory and currently at Genentech, Inc. Additional Salk authors include postdoctoral fellow Nicolas Genoud and senior research assistant Karen Lettieri.

The study, titled ‘The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics,’ was supported by the National Institute for Neurological Disorders and Stroke.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organisation dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, MD, whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Source: Salk Institute for Biological Studies


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