University
of Iowa researchers investigating the basic biology of
cell signaling have made a discovery that may have
therapeutic implications for amyotrophic lateral
sclerosis (ALS) and other neurodegenerative diseases.
The UI team, led by John Engelhardt, Ph.D.,
professor and head of anatomy and cell biology in the
UI Roy J. and Lucille A. Carver College of Medicine,
discovered that two cell-signaling proteins called
Nox1 and Nox2 appear to play an important role in
disease progression of an inherited form of ALS. This
work is published in the Sept. 13 issue of the Journal
of Clinical Investigation.
Deleting either Nox1 or Nox2 genes from mice with
the inherited type of ALS significantly increased the
lifespan of the mice. Nox2 deletion produces the most
dramatic effect, nearly doubling the lifespan of the
mice. In addition, Nox2 deletion dramatically
increased the survival index -- the time from disease
onset to death. This is the first report of a single
gene that affects the survival index in ALS models.
"The findings provide encouraging data that there
are new potential therapeutic targets in ALS," said
Engelhardt, who also is the Roy J. Carver Chair in
Molecular Medicine. "Whether our findings will bear
out in humans still has to be evaluated, but our
results suggest that inhibiting Nox proteins might
significantly enhance survival in ALS."
Nox proteins generate reactive oxygen species (ROS)
-- short-lived, highly reactive molecules. ROS are
essential for normal cell functions including
signaling, but excess ROS can cause damaging oxidative
stress, which contributes to cell damage and death in
neurological diseases.
While studying Nox genes and ROS signaling, the UI
team discovered that superoxide dismutase-1 (SOD-1), a
protein that is mutated in an inherited dominant form
of ALS, interacts with specific structures in cells
that regulate ROS production by Nox proteins.
This unexpected finding suggested that Nox proteins
might be involved in the damaging disease processes at
work in ALS, and prompted the UI team to examine the
effect of removing Nox proteins in mice that have the
ALS-causing SOD-1 mutation.
In addition to finding that deletion of the Nox
genes delays disease onset and enhances survival in
the ALS mice, the UI study also shows that even a 50
percent reduction in Nox2 activity can significantly
delay the onset of motor neuron disease. This means a
drug that only partially inhibits the Nox protein
might still provide a therapeutic benefit.
The UI study suggests that mutations in SOD-1
responsible for certain forms of ALS result in
hyperactive inflammatory responses in the spinal cord
and brain. Excessive ROS production by Nox proteins in
these hyperactive immune cells, appear to be a
significant cause of cellular destruction and loss of
motor neurons. Inflammation and oxidative stress are
thought to play an important role in other
neurodegenerative diseases besides ALS.
"These ROS signaling pathways, and specifically
dysregulation of the pathways, might be a component of
many types of neurodegenerative diseases," Engelhardt
said. "Which means that drugs that might treat ALS by
knocking down these pathways might also be beneficial
for Alzheimer's and Parkinson's disease."
The research team now plans to look for drugs that
inhibit activation of Nox1 and Nox2. They also will
investigate how the SOD-1 mutation leads to
hyperactivation of Nox proteins.
"The closer we get to clarifying the basic
mechanism of how the ALS mutations in SOD-1 lead to
hyperactivation of inflammatory Nox proteins, the
easier it will be to identify drugs that will
interfere with that process," Engelhardt added.
Engelhardt's research colleagues included Jennifer
Marden, Ph.D., and Maged Harraz, Ph.D., who both were
graduate students in Engelhardt's lab when the study
was conducted; Aislinn Williams; Kathryn Nelson;
Meihui Luo; and Henry Paulson, M.D., Ph.D., who was a
UI associate professor of neurology during the study,
and now is a professor of neurology at the University
of Michigan.
The research was funded in part by the Roy J.
Carver Charitable Trust of Muscatine and the National
Institutes of Health.
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Source:
University of Iowa
Published on 20th
September 2007
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