Protein Misfolding, Aggregation, and Degradation 141 MOLECULAR BIOTECHNOLOGY Volume 31, 2005 REVIEW 141 Molecular Biotechnology © 2005 Humana Press Inc. All rights of any nature whatsoever reserved. 1073–6085/2005/31:2/141–150/$30.00 *Author to whom all correspondence and reprint requests should be addressed. 1 Research Unit for Molecular Medicine, Institute for Clinical Medicine, 2 Department of Human Genetics, Aarhus University Hospital SKS, Brendstrupgaardsvej, 8200 Århus N, Denmark. E-mail: Peter.Bross@KI.au.dk.†The present article represents a partly revised and updated version of chapter 1 published earlier in volume 232 of the series Methods in Molecular Biology (Walker, J. M., ed., Humana Press, Totowa, NJ), Protein Misfolding and Disease: Principles and Protocols (Bross, P. & Gregersen N., eds.), pp. 3–16 (2003). Abstract Protein Misfolding, Aggregation, and Degradation in Disease † Niels Gregersen, 1 Lars Bolund, 2 and Peter Bross 1,* Pathologies associated with protein misfolding have been observed in neurodegenerative diseases such as Alzheimer’s disease, metabolic diseases like phenylketonuria, and diseases affecting structural proteins like collagen or keratin. Misfolding of mutant proteins in these and many other diseases may result in premature degradation, formation of toxic aggregates, or incorporation of toxic conformations into struc- tures. We review common traits of these diverse diseases under the unifying view of protein misfolding. The molecular pathogenesis is discussed in the context of protein quality control systems consisting of molecular chaperones and intracellular proteases that assist the folding and supervise the maintenance of the folded structure. Furthermore, genetic and environmental factors that may modify the severity of these diseases are underscored. Index Entries: Conformational disease; protein folding; protein quality control; protein misfolding; protein aggregation; protein aggregation diseases. 1. Introduction During the past 5–10 yr, it has been realized that a large number of diseases with very differ- ent pathologies at the cellular level can be dis- cussed within a common framework of defective protein folding. Although the molecular mecha- nisms by which the pathologies develop are quite different, they can all be viewed as “conforma- tional diseases.” The original concept of confor- mational disease was developed in relation to disorders whose hallmark was intracellular or ex- tracellular accumulation of protein aggregates, such as seen in α-1-antitrypsin deficiency with liver pathology, Alzheimer’s, Parkinson’s, and Huntington’s diseases (AD, PD, and HD, respec- tively) (1–3). The basis for the pathology in these diseases is a cellular inability to degrade misfolded and damaged proteins and formation of cytotoxic intracellular or extracellular oligomers and poly- mers/aggregates. The pathology in these diseases is predominantly determined by the cell damage associated with the aggregation process, thus ex- hibiting what can be considered a “gain-of-func- tion” pathology. Most cases with this type of conformational disease show a multifactorial etiology, involving genetic as well as physiological/environmental components. However, some cases are predomi- nantly genetically determined, such as the early onset forms of Alzheimer’s and Parkinson’s dis- eases, and a few can be considered as classic mono- genic disorders, such as HD and α-1-antitrypsin deficiency. To this last category of monogenic conformational diseases can be added a number of dominantly inherited diseases, such as hereditary forms of keratin and collagen disorders (4,5) as well as familial forms of cardiomyopathies (6), where a misfolded protein coded from a defective