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 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."

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.