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2006 Grant - Prakriya
Aberrant Calcium Signaling Mechanisms in Alzheimer's Disease
Murali Prakriya, Ph.D.
2006 New Investigator Research Grant
Inherited forms of Alzheimer's disease have been traced to mutations in genes for three different proteins. Two of the proteins, called presenilins, are key components of the enzyme that chops up a large protein called amyloid precursor protein (APP), and the other gene is for APP itself. These advances have contributed to the amyloid hypothesis, which posits that a small fragment of APP, called beta-amyloid, is a key trigger of Alzheimer's disease.
But there may be more to Alzheimer's disease than beta-amyloid. Mutations in presenilin genes also upset the balance of calcium in cells. Calcium is a key component in various types of cellular communication systems and is used to trigger the transmission of signals between neurons in the brain-a process that is seriously compromised in Alzheimer's disease.
Murali Prakriya, Ph.D., plans to examine how mutations in presenilin genes may affect the distribution of calcium among various cellular locales, particularly one called the endoplasmic reticulum, a major storage house for calcium. Previously, scientists discovered that presenilin mutations interrupt the store-operated channel, a protein pore embedded in the cell membrane that helps to fill the endoplasmic reticulum with calcium. Curiously, the same mutations appear to enhance release of calcium from the endoplasmic reticulum. Because of technological challenges, scientists have not been able to resolve these two effects, which seem to be contradictory.
Dr. Prakriya and colleagues will use an experimental system that will enable them to measure directly and specifically how presenilin mutations affect endoplasmic reticulum calcium. The researchers will also investigate how compromised store-operated channels affect other cellular processes, such as the switching on and off of genes.