Neurochemistry

Edited by: Steve Bunk THERE THEY ARE: Harvard's Wilma Wasco and colleagues found the subcellular locales of the presenilins, in the endoplasmic reticulum and the Golgi complex. D.M. Kovacs, H.J. Fausett, K.J. Page, T.W. Kim, R.D. Moir, D.E. Merriam, R.D. Hollister, O.G. Hallmark, R. Mancini, K.M. Fstein, B.T. Hyman, R.E. Tanzi, W. Wasco, "Alzheimer-associated presenilins 1 and 2: Neuronal expression in brain and localization to intracellular membranes in mammalian cells," Nature Medicine, 2:224-9, 1996. (Cited in more than 115 publications as of January 1998) Comments by Wilma Wasco, Genetics and Aging Unit and Department of Neurology, Massachusetts General Hospital-East, Harvard Medical School At times, neurochemical research resembles a particularly frustrating detective story, in which each clue creates yet more mystery. Such is the case concerning the principal subject of research in this paper, two novel human genes called the presenilins (PS1 and PS2). Both the normal biological role of the presenilins and the mechanism by which mutations of them exert an effect on familial Alzheimer's disease (FAD) are unknown. Even where presenilins exist in the body had not been verified until a joint team from Harvard Medical School's Massachusetts General Hospital-East and Bristol Myers-Squibb Co.'s laboratory in Wallingford, Conn., undertook the work for this paper. "We were the first to demonstrate the subcellular locales of the presenilins," notes Wilma Wasco, an assistant professor of neurology in the hospital's Genetics and Aging Unit and senior author of this paper. The team showed that the genes are widely expressed inside neurons, in the endoplasmic reticulum (ER), and in the Golgi complex. These findings were essential to a continuing effort to discover the functions of both normal and mutant presenilins by establishing their location. When this research began, it was believed that the vast majority of early-onset FAD, which afflicts people less than 60 years old, is caused by mutations in PS1 and PS2. The presenilins belong to a gene family that is evolutionarily conserved, maintaining its DNA sequence through the generations. The mutant genes seem to be somehow involved in abnormal aggregations in the brains of Alzheimer's patients of amyloid ß-protein 42 (Aß42), a waxy substance consisting of protein and polysaccharides that is widely dispersed in small amounts throughout the body. The normal function of amyloid protein, if any, is unknown. A small percentage of early-onset FAD cases occur when a gene called amyloid ß-protein precursor (APP) mutates to cause increased production of Aß42. However, it is thought that in most cases, mutations in the presenilins may somehow affect the sorting of APP, perhaps by directing it to intracellular environments that are conducive to overproduction of Aß42. Using such techniques as in situ hybridization and immunochemical analyses, Wasco and her colleagues established that the two genes are similar in size, expression, and their localization to intracellular membranes of the ER and Golgi complex. Both those compartments are active in intracellular transport of materials. However, the tests also indicated that the presenilins most likely reside not only in brain regions affected by Alzheimer's disease but also in regions that are relatively spared. "We don't have particularly good explanations for regions of brain cells affected," Wasco acknowledges. Although Wasco's paper doesn't prove that a relationship exists between the location and the function of the presenilins, it does support prior research by others that established significant structural similarities between the presenilins and two gene products of the nematode worm (Caenorhabditis elegans). The two nematode proteins in question, sel-12 and spe-4, are thought to play roles in intracellular trafficking and localization of proteins. After this paper appeared, researchers at the Howard Hughes Medical Institute at Columbia University and at Johns Hopkins University School of Medicine published collaborative evidence that normal human presenilins can substitute for the sel-12 protein in the nematode (D. Levitan et al., Proceedings of the National Academy of Sciences, 93:14940-4, 1996). "Our working hypothesis now is, there is an interaction between presenilin proteins and amyloid proteins," says Wasco. "It looks like the ER compartment in particular could be important. All the players are there: presenilins, APP, and the amyloid peptide itself." Specifically, she thinks presenilins might bind to APP to shuttle it through the ER, and that mutant presenilin could leave the APP stuck in the ER, precipitating the production of too much Aß42. The detection work continues.

Neurochemistry

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