Familial Alzheimer disease (FAD) is an inherited early-onset form of Alzheimer disease. Mutations in the genes that make the proteins presenilin-1 and presenilin-2 have been identified in a substantial proportion of individuals with FAD, but the molecular effects of these mutations have not been clearly defined.
In a study that appears online on April 12 in advance of publication in the May print issue of the Journal of Clinical Investigation, Ilya Bezprozvanny and colleagues from the University of Texas Southwestern, Dallas, used in vitro assays to show that, unlike normal presenilin-1, five of the six FAD-associated mutant forms of presenilin-1 analyzed do not allow calcium to passively leak into the main body of a cell from a compartment known as the ER.
For one mutant, the initial observations were corroborated by the observation that fibroblasts from an individual with FAD who expressed this mutant form of presenilin-1 did not passively leak calcium from the ER. As mutant forms of presenilin-1 associated with a distinct neurological disorder, frontal temporal dementia, did not affect calcium leakage from the ER, the authors conclude that the molecular effects of mutant forms of presenilin-1 are disease specific.
However, further studies are required to determine whether altered calcium leakage actually causes FAD or is just associated with it.
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