Scientists knew it was happening, but it remained a mystery as to what causes cell death in frontotemporal dementia (FTD). A recent study using cell cultures shows the pathological pathway that leads to the cell death as reported in the Journal of Neuroscience.

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.

The cascade of events that leads to FTD begins with the gene progranulin (PGRN), which is 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 researchers showed that low levels of PGRN 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 insoluble clumps of protein. This abnormal process results in the neurodegeneration in people with FTD.

Often, FTD occurs 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, last year 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 found TDP-43 forms clumps in the brain cells of patients with FTD (caused by mutations in the PGRN gene.)