Review: Membrane-associated misfolded protein propagation in natural transmissible spongiform encephalopathies (TSEs), synthetic prion diseases and Alzheimer's disease

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  • This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

Correspondence: Martin Jeffrey, Lasswade Laboratory, Animal Health and Veterinary Laboratories Agency, Pentlands Science Park, Bush Loan, Penicuik EH26 0PZ, Midlothian, UK. Tel: +44 131 445 6169; Fax: +44 131 445 6166; E-mail: martin.jeffrey@ahvla.gsi.gov.uk

Abstract

Protein misfolding has long been recognized as a primary cause of systemic amyloidosis and, increasingly, template-mediated misfolding of native host proteins is now also considered to be central pathogenetic events in some neurodegenerative diseases. Alzheimer's disease, naturally occurring transmissible spongiform encephalopathies (TSEs) and experimental disorders caused by misfolded prion protein (PrP) generated in vitro all share an imbalance of protein synthesis, aggregation and clearance that leads to protein aggregation, prompting some to suggest that Alzheimer's disease is caused by a prion-like mechanism. In TSEs, the host-coded, glycosyl-phosphoinositol (GPI) membrane-anchored prion protein (PrPc) is misfolded into disease-associated, putatively infectious aggregates known as prions. In Alzheimer's disease the membrane-spanning Alzheimer's precursor protein (APP) is progressively cleaved within the plasmalemma to form peptide fragments that can form pathogenic extracellular aggregates while microtubule-associated tau proteins may also aggregate within neurones. Oligomeric peptides and full-length misfolded PrP show a common potential to convert native protein and aggregate on plasma membranes before subsequent release to form amyloid fibrils in the extracellular space. However, the nature, membrane topography and processing of the precursor and propagated proteins in prion and Alzheimer's disease all differ, and each group of diseases has distinctive spectra of additional pathological changes and clinical signs suggesting that fundamentally different disease mechanisms are involved.

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