Peptide aggregation in neurodegenerative disease.
In the not-so-distant past, insoluble aggregated protein was considered as uninteresting and bothersome as yesterday's trash. More recently, protein aggregates have enjoyed considerable scientific interest, as it has become clear that these aggregates play key roles in many diseases. In this review, we focus attention on three polypeptides: beta-amyloid, prion, and huntingtin, which are linked to three feared neurodegenerative diseases: Alzheimer's, "mad cow," and Huntington's disease, respectively. These proteins lack any significant primary sequence homology, yet their aggregates possess very similar features, specifically, high beta-sheet content, fibrillar morphology, relative insolubility, and protease resistance. Because the aggregates are noncrystalline, secrets of their structure at nanometer resolution are only slowly yielding to X-ray diffraction, solid-state NMR, and other techniques. Besides structure, the aggregates may possess similar pathways of assembly. Two alternative assembly pathways have been proposed: the nucleation-elongation and the template-assisted mode. These two modes may be complementary, not mutually exclusive. Strategies for interfering with aggregation, which may provide novel therapeutic approaches, are under development. The structural similarities between protein aggregates of dissimilar origin suggest that therapeutic strategies successful against one disease may have broad utility in others.
Murphy
Regina M
RM
Department of Chemical Engineering, University of Wisconsin, Madison 53706, USA. murphy@che.wisc.edu
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D002417:Cattle; D006801:Humans; D000071058:Huntingtin Protein; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D020539:Sequence Analysis, Protein; D013329:Structure-Activity Relationship
D000682:Amyloid; D016229:Amyloid beta-Peptides; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011328:Prions