|Scientists Suggest New Pathway Causing Cell
Death in Dementia
Scientists have discovered a link between a mutated gene and a
protein found in dead brain cells of people who suffer from a form
of dementia and other neurological disorders. The finding, reported
in the Sep. 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. The study was funded by the National Institute
on Aging (NIA) at the National Institutes of Health (NIH).
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.
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 Alzheimerís 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. Petrucelliís 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
The NIA leads the federal government effort conducting and supporting
research on the biomedical and social and behavioral aspects of
aging and the problems of older people. For more information on
aging-related research and the NIA, please visit the NIA website
at www.nia.nih.gov. The NIA
provides information on age-related cognitive change and neurodegenerative
disease specifically at its Alzheimer's Disease Education and Referral
(ADEAR) Center site at www.nia.nih.gov/alzheimers.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.