New Discovery Could Lead to Therapy for ALS and Frontotemporal Dementia (FTD)
By Regina Sass
Published Sep 27, 2007

New Discovery Could Lead to Therapy for ALS and Frontotemporal Dementia Results from a new study just released by the Mayo Clinic in Jacksonville, Florida, could lead to new drug therapy for frontotemporal dementia (FTD), and amyotrophic lateral sclerosis -Lou Gehrig's disease.

They have discovered a link exists between a mutated gene and a protein that is found in the dead brain cells of patients with one form of dementia as well as other neurological disorders.

The study was done in cell cultures and it shows that there is a cell death pathway involved. It all begins with the mutation of a gene called progranulin (PGRN). It is located on chromosome 17. Under normal conditions, high level of PGRN are in a cell to help it grow and survive. But when the progranulin gene mutates, it causes a protein, TDP-43, to be separated into 2 fragments. These fragments migrate from their assigned location in the nucleus to the outside and into the cytoplasm that surrounds the cell. Once here they form insoluble clumps of protein. And this process results in neurodegeneration in patients with FTD or ALS.

FTD attacks the frontal and the temporal lobes in the brain. It causes the persons personality to change as well as uninhibited and socially inappropriate behavior/ In the late stages of the disease, patients suffer from loss of memory and speech as well as motor skills. It is the second most common cause of dementia in people who are under the age of 65, the first one being Alxheimer's. ALS is a progressive and fatal disease of the motor meurons that are located in the spinal cord.

FTD often surfaces in patients with a family history of dementia, and in those families, many of the cases have been traced to a regiion of DNA on chromosome 17. And also, many of them are caused by a mutation of a gene called tau in the same region.

There were other cases of FTD that were linked to this same region of the same chromosome, but the exact cause was not known. They knew the region, but they were not connected to the known gene, tau.

Then, in 2006 a study discovered that families with a history of the inherited FTD, but did no have any mutations in the tau gene, do have a mutation in the PGRN gene. The two genes are very close together on the same chromosome.

That study was followed up with a second one that same year and this one found TDP-43 in clumps the form in the cells of the brains of ALS patients and patients with the form of FTD caused bye the PGRN gene mutations.

In the study just released, they have been able to show just how the PGRN gene mutations causes the formation of the clumps of TDP-43 fragments and the eventual death of the brain cells.

The next step will be to find what needs to be done to develop a new therapy.

The lead researchers on the project are Leonard Petrucelli, Ph.D., and Dennis W. Dickson, M.D, of the Mayo Clinic in Jacksonville, Fla. and Marcelle Morrison-Bogorad, Ph.D., Director of the Neuroscience and Neuropsychology

The study was funded by the National Institute on Aging (NIA) at the National Institutes of Health (NIH) and supported by the Mayo Clinic Foundation

Source National Institute of Health http://www.nih.gov/

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