Oct. 1, 2007 

Mariana Iglesias
507-284-5005 (days)
507-284-2511 (evenings)
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For Immediate Release 

Loss of gene leads to protein splicing and buildup of toxic proteins in neurons 

JACKSONVILLE, Fla. - Researchers at Mayo Clinic in Jacksonville have discovered
how loss of a gene can lead to accumulation of toxic proteins in the brain,
resulting in a common dementia, and they say this mechanism may be important in
a number of age-related neurological disorders. 

In the Sept. 26 issue of the Journal of Neuroscience, the scientists demonstrate
that absence of a gene known as progranulin leads to errant splicing of a
protein that usually operates within the nucleus of a nerve cell (neuron). When
cut these proteins move into the body of the cell, and begin to stick together
and form a thicket that grows, eventually disrupting the normal functioning of
the neuron, the researchers say. 

Clumps of this protein, TDP-43, have been found in a number of older age
dementias, including Alzheimer's Disease (AD), Frontal Temporal Dementia (FTD),
and in amyotrophic lateral sclerosis (ALS). 

Not only does the study potentially explain why TDP-43 pathology is present in a
number of neurodegenerative diseases, it also offers new research routes to take
in looking for beneficial treatments, says the study's lead investigator,
Leonard Petrucelli, Ph.D. "Our work opens opportunities on possible future
therapeutic applications, from approaches to novel drug discovery to the
continued exploration of cell survival systems," he says. 

Mayo investigators filled in this piece of the dementia puzzle by exploring
possible connections between two recent ground-breaking discoveries. In July,
2006, Mayo researchers reported in Nature that a form of FTD not caused by tau
accumulation in neurons was due to mutations in the progranulin gene.
Progranulin produces a protein that helps neurons survive, and so far, the
research group has found more than 40 different mutations in the gene can
directly cause FTD. 

The second study, reported in October, 2006, in Science by researchers at the
University of Pennsylvania School of Medicine, found that the protein clogging
brains of patients with FTD and ALS is TDP-43. The protein was recovered from
post-mortem brain tissue and was found only in areas affected by the diseases.
For example, in ALS patients it was found in the spinal cord motor neurons which
control movement, and in patients with FTD, which is second most common form of
dementia in people under age 65, clumps of TDP-43 were found in the frontal and
temporal lobes which control the judgment and thought process disrupted in the
disease. In its normal state, TDP-43 is believed to help genes produce proteins.


In this study, Mayo researchers investigated whether progranulin is involved in
TDP-43 processing. Suppressing progranulin expression in neurons led to
accumulation of TDP-43 fragments, they found, and further discovered that this
cleavage depends on the caspase 3 enzyme. Caspases cut other proteins and thus
play a crucial role in pushing a cell to die when it needs to. It makes sense
that these caspase might be activated when progranulin is mutated, Dr.
Petrucelli says, because loss of progranulin can activate cell death signaling.
"We are now looking into how mutations in progranulin lead to an increase in
caspase activity," he says. "Progranulin could be acting a protective chaperone
where it binds to TDP-43, and may protect it from cleavage." 

Theoretically, suppression of caspase 3 might stop the cutting and accumulation
of TDP-43, but such a strategy could not work clinically given that caspases are
needed throughout the body for normal functioning, Dr. Petrucelli says.
"However, it might be possible to identify other compounds that specifically
prevent the fragmentation and redistribution of TDP-43, and that is an issue we
are now studying." 

At this point, researchers don't know if progranulin mutations are present in
ALS or in AD. 

The study was funded by the Mayo Clinic Foundation and by the National Institute
on Aging, part of the National Institutes of Health. In this study, Yong-Jie
Zhang, Ph.D., and Ya-fei Xu, M.D., both of whom contributed equally as first
authors, and other Mayo Clinic, Jacksonville, contributors include Dennis
Dickson, M.D., and Rachel Bailey, B.S. Other authors include Chad Dickey, Ph.D.,
from the University of South Florida; Emanuele Buratt,i Ph.D., and Francisco
Baralle, M.D., from the International Center for Genetic Engineering and
Biotechnology in Trieste, Italy; and Stuart Pickering-Brown, Ph.D., from the
University of Manchester in the United Kingdom. 

Mayo Clinic, through a dedicated focus on individual patient needs, provides
diagnostic and treatment services in every sub-specialty at its locations in
Rochester, Minnesota; Jacksonville, Florida and Phoenix and Scottsdale, Arizona.

# # #

To obtain the latest news releases from Mayo Clinic, go to
<file://www.mayoclinic.org/news> www.mayoclinic.org/news. MayoClinic.com (
<file://www.mayoclinic.com> www.mayoclinic.com) is available as a resource for
your health stories.



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