Neurodegenerative Diseases: Progranulin (PGRN) Mutation and TDP-43
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."
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