May 30, 2012 in
Neuroscience (Medical Xpress) -- A
protein produced by the central nervous system’s support cells seems to play
two opposing roles in protecting nerve cells from damage, an animal study by
Johns Hopkins researchers suggests: Decreasing its activity seems to trigger
support cells to gear up their protective powers, but increasing its activity
appears to be key to actually use those powers to defend cells from harm. Seth Blackshaw, Ph.D., an associate professor
in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University
School of Medicine, explains that researchers have long suspected that central
nervous system cells called glia play an important role in saving nerve cells
from almost certain death after either an acute injury, such as a blow to the
head, or chronic damage, such as that caused by Alzheimer’s or Parkinson’s
disease. Glia — named after the Greek word for glue, since decades ago they
were thought to play a very passive role in holding the central nervous system
together — respond to an assault on nearby neurons in a dramatic way, puffing
up to a larger size and turning off several genes involved in routine
maintenance functions. Previous research in cell cultures containing
both neurons and glia showed that when the entire group was exposed to an assault,
the reaction of the glia seemed to drive a response that protects cells from
subsequent damage. However, Blackshaw says, it’s been unclear exactly what glia
are doing when they change in size and gene expression. Even whether this
response is actually important for protection was uncertain, he adds, since
it’s been impossible to study this so-called glial reactivity without treating
whole tissues that include neurons and other types of cells that may exert
their own protective effects. Hoping to find a way to trigger glial
reactivity without assaulting entire tissues, Blackshaw and his colleagues
searched for proteins that could play an important role in this response. The
team used Mueller glia as their model system. These glia are the most abundant
type in the retina, and are highly likely to behave like other glia throughout
the central nervous system, Blackshaw says. The
researchers’ investigation eventually zeroed in on a protein called Lhx2. When
they bred mutant mice that selectively lacked Lhx2
in the glia of the eye, these cells displayed the physical and
genetic characteristics of being reactive all the time, even without any
damaging stimulus. However, to the researchers’ surprise, hitting the mutant
animals’ eyes with extraordinarily bright light caused considerably more damage
to their retinas compared to the same stimulus in normal mice. To
understand why these reactive glia didn’t produce the expected protective
response, the researchers looked for other pro-survival proteins that glia
produce under assault. In the mutant animals, these other proteins were
conspicuously missing, Blackshaw says, suggesting that Lhx2 is necessary for
glia to produce other protective proteins. “Lhx2 seems to be a master regulator of glial reactivity, and we’ve shown
here that it has two faces,” Blackshaw says of these results, reported in the
March 20 issue of the Proceedings of the National Academy of Sciences. While
the protein’s absence seems to be critical for triggering the physical and
genetic changes glia use to bring their protective proteins to bear to help
neurons survive, its presence is vital to produce these proteins in the first
place. Levels of Lhx2 activity likely dip and then increase in glia exposed to
an attack, he says, explaining both the initial glial reactivity researchers
see under a microscope as well as the resulting neural protection. Once
researchers understand this mechanism better, Blackshaw adds, they may be able
to craft drugs that stimulate glia to pump out more pro-survival proteins,
making novel therapies for neurodegenerative diseases. Other Hopkins
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