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New protein identified in Alzheimer's disease
Nicastrin may be involved in processing disease-related proteins
Edward R. Winstead

The list of proteins suspected in Alzheimer's disease just got a little longer. An international team of researchers reports this week that a protein called nicastrin may be involved in generating the protein fragments that accumulate in the brains of individuals with the disease. The group is headed by Peter St. George-Hyslop, of the Centre for Research in the Neurodegenerative Diseases and the University of Toronto, Canada.

The discovery may give drug developers a new target.

Although its specific function is unclear, nicastrin appears to be necessary for processing disease-related proteins, according to a paper in the current issue of Nature. Many studies in recent years have attempted to explain how protein fragments called amyloid-beta proteins are generated. One view of the disease holds that these fragments, which comprise the 'plaques' characteristic of brain tissue in Alzheimer's patients, are essentially generated by the cleavage of their larger precursor, amyloid precursor protein, or AAP.

At least two proteins (presenilin 1 and presenilin 2) have been implicated in the creation of amyloid-beta proteins from AAP. Now, St. George-Hyslop's group proposes that nicastrin is an essential partner in this poorly understood process. Nicastrin and presenilin, they suggest, form 'functional complexes' that serve as protein-processing machinery.

The researchers named the new protein for the Italian village of Nicastro, where Alzheimer's disease was reported in descendents of an extended family nearly 40 years ago. These early reports involved presenilin-associated forms of the disease and prompted a search for the molecular machinery involved, the authors write in Nature.

The researchers do not know if variants of the nicastrin gene are associated with an increased susceptibility to Alzheimer's. Preliminary studies of a group of individuals with an inherited form of the disease failed to turn up mutations, or polymorphisms, in the gene. In an accompanying News & Views article, Dale Schenk, of Elan Pharmaceuticals, notes that the discovery provides a new molecular target for the design of drugs to treat this neurodegenerative disorder.

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Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and bAPP processing. Nature 407, 48-54 (September 7, 2000).

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