Pin1: a New Genetic Link Between Alzheimer's Disease, Cancer and Aging

Epidemiologic data suggest that people who develop neurodegenerative diseases of aging have a decreased risk of cancer. This is intriguing, since there is growing evidence that neurodegeneration and carcinogenesis share a number of biological pathways, such as abnormal entry into the cell cycle. The unique enzyme Pin1 plays a key role in the pathogenesis of Alzheimer's disease and many human cancers. Pin1 acts on proteins after they have been phosphorylated at specific sites, causing them to twist between two completely distinct conformations. This conformational change profoundly affects protein activity and is a major method of cellular signaling and regulation. In the neuron, Pin1 promotes cellular health by restoring phosphorylated tau and amyloid precursor protein to a functional state. The loss of active Pin1 leads to the accumulation of abnormal tau and the overproduction of β-amyloid, the cardinal features of Alzheimer's disease. Pin1 also regulates the cell cycle and is a necessary enzyme for cell division. Over-expression of Pin1 can promote oncogenesis through a number of signaling pathways. We hypothesize that Pin1 might help explain an inverse relationship between Alzheimer's disease and cancer. Pin1 deficiency in mice leads to an early-aging phenotype, suggesting that Pin1 activity is necessary for healthy aging and the prevention of age-related diseases. We review the role of Pin1 in cancer and neurodegeneration, discuss the relationship between Pin1 and aging, and explore its potential as a diagnostic and therapeutic target.