Scientists Suggest New Pathway Causing Cell Death in Dementia
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found in dead brain cells of people who suffer from a form of dementia
and other neurological disorders. The finding, reported in the Sept.
26, 2007, issue of the Journal of Neuroscience, demonstrates for the
first time a pathological pathway that ultimately results in cell
death related to frontotemporal dementia (FTD) and amyotrophic lateral
sclerosis (ALS, also known as Lou Gehrig's disease). The discovery
could eventually play a role in the design of new drug therapies.
Leonard Petrucelli, Ph.D., and Dennis W. Dickson, M.D, of the Mayo
Clinic in Jacksonville, Fla., led the international team of scientists
in the study supported by the Mayo Clinic Foundation and funded by the
National Institute on Aging (NIA), part of the National Institutes of
Health (NIH).
The study, in cell cultures, showed that a cell death pathway is
involved. A cascade of events begins with a mutation in the gene
progranulin (PGRN) located on chromosome 17. Normally, high levels of
PGRN exist in a cell to promote cell growth and survival. But when
progranulin gene mutations occur, low levels of PGRN result. The
investigators showed that this causes a protein called TDP-43 to be
cut into two fragments. These fragments then migrate from their usual
location in the nucleus into the surrounding cytoplasm of the cell
where they form inclusions, or insoluble clumps of protein. This
abnormal process results in the neurodegeneration in people with FTD
and ALS.
"This research defines a novel disease mechanism that may be important
in a number of age-related neurological diseases," said Marcelle
Morrison-Bogorad, Ph.D., Director of the Neuroscience and
Neuropsychology Program at the NIA. "It opens a window on possible
future applications, from approaches to novel therapeutic targets to
the continued exploration of cell survival systems."
FTD affects the frontal and temporal lobes of the brain. It causes
changes in personality, uninhibited and socially inappropriate
behavior, and in late stages, loss of memory, motor skills and speech.
After Alzheimer's disease, it is the most common cause of dementia in
people under age 65. ALS is a progressive, fatal disease of the spinal
cord motor neurons.
Many FTD cases occur in families with a history of dementia. Among
those families, many of the cases have been linked to a region of DNA
on chromosome 17. Many of these cases are caused by mutations in a
gene called tau in this region. Until recently, the cause of the
remaining FTD cases linked to the same region of this chromosome was
not known. However, in 2006, a study found that families with
inherited FTD but no mutations in the tau gene have a mutation in the
PGRN gene, which lies near the tau. A second study that year found
TDP-43 in clumps that form in brains cells of patients with ALS and
the form of FTD caused by mutations in the PGRN gene. Dr. Petrucelli's
study is the first to show how mutations in the PGRN gene cause the
formation of clumps of TDP-43 fragments, and ultimately, death of
brain cells.
"These data provide much needed insight into mechanisms in disorders
associated with TDP-43," said Mayo's Petrucelli. "The science is
moving very quickly, but many questions remain to be explored."