ScienceWeek

ROGUE PROTEINS, PRIONS, AND ALZHEIMER'S DISEASE

The following points are made by A. Aguzzi and C. Haass (Science 2004 302:814):

1) The key pathogenetic factors of both Alzheimer's disease (AD) and prion disorders (PrD) are neuronal membrane proteins: the amyloid precursor protein APP and the prion protein PrPC. Their adducts, A-beta and PrP-Sc, are major constituents of the deposits littering the brain of AD and PrD patients. The role of A-beta and PrP-Sc in disease was validated by the discovery that mutations of the respective genes result in autosomal-dominant AD and PrD.

2) In addition to APP, positional cloning of the genes causing familial AD led to the identification of the presenilins (1), which encode the presumed proteolytic core of the gamma-secretase (2). This landmark discovery immensely accelerated AD research, and its reverberations span from developmental biology (3) to microbiology (4-5), basic cell biology, and protease biochemistry.

3) Two decades after Prusiner postulated that PrPSc is identical with the prion [i.e., the infectious principle), we still have an incomplete idea of the mechanism by which PrPC is converted into a pathogenic moiety. PrPC is necessary for replication of the infectious agent and for pathogenesis. However, human genetics was less helpful in PrD than in AD. All cases of familial PrD segregate with PrPC mutations, and no relevant genetic or physical interactors were identified. A report that histocompatibility loci would be linked to PrD susceptibility was not confirmed by others. Thus, a number of basic questions are still open. Nevertheless, despite fundamental differences in their biochemistry and genetics, the recent advances in prion and AD research suggest that AD and PrD converge in many pathogenetic aspects and may even be amenable to similar therapeutic principles.

4) In summary: The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the A-beta peptide, whereas PrPC begets the malignant prion protein PrP-Sc. Both A-beta and PrP-Sc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.

References (abridged):

1. R. Sherrington et al., Nature 375, 754 (1995)

2. M. S. Wolfe et al., Nature 398, 513 (1999)

3. D. Selkoe, R. Kopan, Annu. Rev. Neurosci. (2003)

4. C. Haass, H. Steiner, Trends Cell Biol. 12, 556 (2002)

5. H. Steiner et al., Nature Cell Biol. 2, 848 (2000)

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