MGH Researchers Connect Alzheimer's Mutations To Cell-Death Process

In the July 18 issue of Science, the scientists describe their studies of the protein products of two genes called presenilins. Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Unit and leader of the study, explains that this work is the first to directly and clearly connect these Alzheimer's genes with apoptosis, which has long been suspected as a mechanism in several neurodegenerative diseases.

"Both presenilins now join a select group of proteins which help bring about cell death," Tanzi says. "In the brain, this process usually takes place during early growth, when extra neurons [brain cells] die to assure proper development. We hypothesize that in older individuals the cell-death pathway becomes reactivated in certain neurons, especially in regions affected by Alzheimer's. While mutations in these genes appear to speed up this process and cause early-onset Alzheimer's, environmental factors could set off the process in sporadic cases of the disease. This discovery creates an excellent target for new drug development."

Presenilin (PS)1, located on chromosome 14, and PS2, located on chromosome 1, both were discovered in 1995 by multi-institutional collaborations including members of the MGH research team. When mutated, PS1 (which also has been called S182 and STM-1) is believed to cause roughly 50 percent of inherited, early-onset Alzheimer's, while PS2 (also called STM-2) is associated with a much smaller proportion. Defects in both genes are directly causative; anyone who inherits a mutated form of the gene is destined to develop the disease, usually before age 65.

When apoptosis takes place, many of the proteins that make up a cell are clipped apart by certain enzymes called caspases. Although clipping proteins into smaller fragments is a normal part of cellular metabolism, apoptosis-associated clipping takes place at alternative locations along the protein strand, changing the molecular message carried by the protein and eventually leading to the cell's death. The new findings suggest that presenilin proteins are cell-death substrates -- proteins that are clipped by caspases to carry out the process of cell death.

To confirm the presenilin proteins' cell-death role, the MGH researchers analyzed the proteins produced by cultured neurons under normal conditions and after apoptosis was induced by substances that trigger the process. They identified the sites at which both presenilins were clipped in normal cellular proces sing by isolating the two fragments the original proteins were cut into. When cells undergo apoptosis, the researchers found, both presenilins are clipped in alternative loca tions, producing different protein fragments that contribute to the cell-death process.

The researchers then looked at cells carrying a PS2 mutation found in a number of families with early-onset Alzheimer's. When both normal cells and mutated cells were induced to make PS2, the mutated PS2 was three times more likely to be clipped in the location associated with the cell-death pathway than was the normal PS2.