Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions

For many decades, clinicians have been aware of the formation of insoluble protein aggregates in particular diseases. For example, in sickle cell disease, the polymerization of sickle hemoglobin into fibrils in the deoxygenating environment of the microvasculature causes sickling of red cells and vaso-occlusion (1). In the most common form of α1-antitrypsin deficiency (see Perlmutter, this Perspective series, ref. 2), the presence of α1-antitrypsin inclusions in the endoplasmic reticulum (ER) of hepatocytes is associated with deficient release of the enzyme into the circulation, placing both the inclusion-laden liver and the antitrypsin-deficient lung at risk for damage (3). In Alzheimer disease (see Selkoe, this series, ref. 4), the presence in the CNS of β-amyloid–containing plaques is associated with neurodegeneration and dementia (5). Similarly, other neurodegenerative diseases have recently been discovered to involve protein aggregation. For example, prion diseases such as Creutzfeldt-Jacob disease and bovine spongiform encephalopathy are associated with amyloid deposits of the PrP protein (6). Polyglutamine repeat diseases such as Huntington disease are likewise associated with neuronal cytosolic and intranuclear inclusions (7). These inclusions are composed of fibrils that stain similarly to amyloid (8). Finally, in Parkinson disease, inclusions known as Lewy bodies, found in the cytoplasm of cells of the basal ganglia, include amyloid-like aggregates of the protein α-synuclein (9, 10).