Scientists have discovered that a gene linked to Alzheimer's disease may play a beneficial role in cell survival by enabling neurons to clear away toxic proteins. A study funded by the National Institute on Aging (NIA), part of the National Institutes of Health, shows the presenilin 1 (PS1) gene is essential to the function of lysosomes, the cell component that digests and recycles unwanted proteins. However, mutations in the PS1 gene-a known risk factor for a rare, early onset form of Alzheimer's disease-disrupt this crucial process.

Ralph Nixon, M.D., Ph.D., of the Nathan Kline Institute, Orangeburg, New York, and New York University Langone Medical Center, directed the study involving researchers from the United States, Europe, Japan and Canada. Also supported in part by the Alzheimer's Association, the study appeared in the June 10, 2010, online issue of Cell.

Researchers have theorized for more than a decade that PS1 mutations linked to early-onset Alzheimer's, a rare form of the disease that usually affects people between ages 30 and 60, may trigger abnormally high levels of beta-amyloid protein to clump together in the brain.

Amyloid deposits and tau protein tangles are hallmarks of both early-onset and the sporadic, more common form of the disease found in people aged 60 and older. These new findings, however, suggest PS1 mutations may play a more general role in the development of early-onset Alzheimer's.

"This study expands our understanding of the role presenilin 1 mutations may play in Alzheimer's pathology," said NIA Director Richard J. Hodes, M.D. "While more research is needed, lysosome disruption may be worth exploring as a potential target for new therapeutics to treat, prevent or delay this progressive and debilitating disease."

Working in cells from Alzheimer's disease mouse models and in skin cells from Alzheimer's patients with the mutated gene, the researchers found: The PS1 gene activates lysosome enzymes that digest waste proteins during a process called autophagy. This is the cell's main method of recycling unwanted proteins and other cellular debris. While these waste proteins occur naturally, they are overproduced in neurological disorders like Alzheimer's and Parkinson's disease, and can be toxic to brain cells; Mutations in the PS1 gene disrupt autophagy. This impairs the ability of neurons to remove waste proteins and other debris. Neurons then may fill with sacs containing potentially toxic amyloid fragments and other unwanted proteins.

Other genetic mutations may be risk factors for similar disruptions to autophagy found in the more common, sporadic form of the disease in people age 60 and older, and in other neurological disorders like Parkinson's disease.

"It has become increasingly clear that many factors may drive the development and progression of this very complex disease," said Nixon, the principal investigator. "I believe we will need to explore an array of therapeutic targets, including ones to normalize or moderate disrupted autophagy."