PA) - Researchers at the University of Pennsylvania School
of Medicine have discovered the major disease protein for
two neurodegenerative disorders: a type of frontotemporal dementia
(FTD) and amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s
disease. A protein called TDP-43 was found to accumulate abnormally
in post-mortem brain tissue from individuals diagnosed with either
disease. The misfolded, disease protein was recovered from only
affected central nervous system regions, which include the hippocampus,
neocortex, and spinal cord.
These findings open up new avenues of research into how the crumpling,
or misfolding, of specific brain proteins (TDP-43) leads to strange,
and sometimes even criminal behavior (in FTD), as well as paralysis
(in ALS), which depends upon whether these toxic waste products
get dumped in the frontal and temporal lobes (the part of brain
controlling judgment and comportment), or the spinal cord motor
neurons (the control centers regulating the ability to walk, run,
and other types of movement).
A connection between these two disorders has long been sought and
TDP-43 is the common pathologic protein linking them. The researchers
published their findings in the October 6, 2006 issue of Science,
and have resolved a long-standing mystery that many consider one
of the last major enigmas about the relationship of FTD to ALS.
“It’s very exciting that we finally made the connection
between dementia and motor neuron disease,” says Virginia
Lee, PhD, Director of the Center for Neurodegenerative
Disease Research at Penn. FTD is a complex group of disorders -clinically,
genetically, and pathologically - and is the most common cause of
dementia in people under the age of 65, after Alzheimer’s
disease. Progressive changes in social, behavioral, and language
skills are part of FTD; some patients also develop motor neuron
disease. In some patients diagnosed with ALS - a progressive neurological
disorder that destroys motor neurons - dementia can also be a later
While most people have heard of ALS because it affected baseball
great Lou Gehrig, fewer people have heard of FTD; it is less common,
overall, than other dementias such as Alzheimer’s disease.
“However, another reason for FTD’s relative obscurity
is also undoubtedly the shame family members experience with the
strange and, at times, bizarre behavior of patients, including disturbing
obsessions, larceny, or even sexual deviancy, that may bring the
patient to the attention of the legal system rather than to the
healthcare system,” notes coauthor John Trojanowksi,
MD, PhD, Director of the Institute on Aging at Penn.
Misfolded proteins are a common mechanism in neurodegenerative diseases.
The misfolded proteins are tagged for recycling by the cell with
another protein called ubiquitin. However, in neurodegenerative
diseases these tagged proteins aggregate in the neurons of the brain
and spinal cord and act like toxic waste dumps that become progressively
more widespread and toxic. Many misfolded disease proteins have
been identified and targeted for drug development in other neurodegenerative
disorders; however, identifying the disease protein in the most
common form of FTD and ALS remained elusive.
“Clinically there’s overlap in these two disorders,
so it was very tantalizing to see if there was anything to link
them biochemically,” says Lee. Indeed, this overlap suggested
different manifestations of the same disorder.
To identify the protein, the group first made antibodies to the
tagged, misfolded protein common to tissue samples from both disorders.
“We then took brain extract containing the mystery protein
and injected it into mice to develop the monoclonal antibodies that
recognize TDP-43,” explains Lee. The researchers then used
antibodies against TDP-43 in post-mortem brain tissue samples and
found that all 72 cases of FTD or ALS examined contained misfolded
TDP-43. “Since many cases were studied, the data became very
compelling,” recalls Lee.
TDP-43 is a known protein with multiple functions and is widely
expressed throughout the body, in the nucleus of many cell types.
Its function has been implicated in editing the transcription of
the genetic code and also as a scaffold protein for another motor
neuron protein. The discovery that TDP-43 is the disease protein
in the most common form of FTD and ALS will drive renewed efforts
to discover more effective treatments for these otherwise lethal
This research was funded by the National Institute on Aging. Coauthors,
in addition to Lee and Trojanowski, are first authors Manuela Neumann,
Deepak M. Sampathu, and Linda K. Kwong, all from Penn, as well as
Matthew C. Micsenyi, Thomas T. Chou, Jennifer Bruce, Theresa Schuck,
Murray Grossman, Christopher M. Clark, and Leo F. McCluskey, also
from Penn. Bruce L. Miller, University of California, San Francisco;
Eliezer Masliah, UC, San Diego; Ian R. Mackenzie and Howard Feldman,
University of British Columbia; Wolfgang Feiden, University of Saarland
(Homburg); and Hans A. Kretzschmar, Ludwig-Maximilians University
(Munich) were also coauthors.
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